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Ophthalmic Molecular Genetics |

BBS1 Mutations in a Wide Spectrum of Phenotypes Ranging From Nonsyndromic Retinitis Pigmentosa to Bardet-Biedl Syndrome FREE

Alejandro Estrada-Cuzcano, BSc; Robert K. Koenekoop, MD, PhD; Audrey Senechal, PhD; Elfride B. W. De Baere, MD, PhD; Thomy de Ravel, MD, PhD; Sandro Banfi, MD; Susanne Kohl, MD; Carmen Ayuso, MD, PhD; Dror Sharon, PhD; Carel B. Hoyng, MD; Christian P. Hamel, MD, PhD; Bart P. Leroy, MD, PhD; Carmela Ziviello, BS; Irma Lopez, PhD; Alexandre Bazinet, MD; Bernd Wissinger, PhD; Ieva Sliesoraityte, MD; Almudena Avila-Fernandez, PhD; Karin W. Littink, MD, PhD; Enzo M. Vingolo, MD; Sabrina Signorini, MD, PhD; Eyal Banin, MD, PhD; Liliana Mizrahi-Meissonnier, PhD; Eberhard Zrenner, MD; Ulrich Kellner, MD; Rob W. J. Collin, PhD; Anneke I. den Hollander, PhD; Frans P. M. Cremers, PhD; B. Jeroen Klevering, MD, PhD
[+] Author Affiliations

Author Affiliations: Departments of Human Genetics (Mr Estrada-Cuzcano and Drs Littink, den Hollander, Collin, and Cremers) and Ophthalmology (Drs Hoyng, Collin, den Hollander, and Klevering), Radboud University Nijmegen Medical Centre, Nijmegen Center of Molecular Life Sciences (Mr Estrada-Cuzcano and Drs Collin, den Hollander, and Cremers), Radboud University Nijmegen, Nijmegen, the Netherlands; McGill Ocular Genetics Laboratory, Montreal Children's Hospital, McGill University Health Centre, Montreal, Quebec, Canada (Drs Koenekoop, Lopez, and Bazinet); Institut National de la Santé et de la Recherche Médicale (INSERM) U583, Institute for Neurosciences of Montpellier, Montpellier, France (Dr Senechal); Centre for Medical Genetics (Drs De Baere and Leroy), Department of Ophthalmology (Dr Leroy), Ghent University Hospital and Ghent University, Ghent, Belgium; Department of Clinical Genetics, Center for Human Genetics, University Hospital Leuven, Leuven, Belgium (Dr de Ravel); Telethon Institute of Genetics and Medicine (Dr Banfi and Ms Ziviello), and Medical Genetics, Department of General Pathology, Second University of Naples (Dr Banfi), Naples, Italy; Molecular Genetics Laboratory, University Eye Hospital, Tübingen, Germany (Drs Kohl and Wissinger); Genetics Department, Instituto de Investigación Sanitaria (IIS)–Fundación Jimenez Díaz, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) Unit, Madrid, Spain (Drs Ayuso and Avila-Fernandez); Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel (Drs Sharon, Banin, and Mizrahi-Meissonnier); Department of Ophthalmology, Centre de Reference Maladies Sensorielles Genetiques, Hopital Gui de Chauliac, and School of Medicine, Montpellier University 1, Montpellier, France (Dr Hamel); Unit of Pathophysiology of Vision, Institute for Ophthalmic Research, Centre for Ophthalmology, University Tübingen, Tübingen (Drs Sliesoraityte and Zrenner); Department of Ophthalmology, A. Fiorini Hospital, Polo Pontino, University of Rome “La Sapienza,” Rome, Italy (Dr Vingolo); Unit of Child Neurology and Psychiatry, Istituto Ricerca e Cura a Carattere Scientifico, C. Mondino Institute of Neurology, University di Pavia, Pavia, Italy (Dr Signorini); and Center of Rare Retinal Disease, AugenZentrum Siegburg, Siegburg, Germany (Dr Kellner).


SECTION EDITOR: JANEY L. WIGGS, MD, PhD

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Arch Ophthalmol. 2012;130(11):1425-1432. doi:10.1001/archophthalmol.2012.2434.
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Objective To investigate the involvement of the Bardet-Biedl syndrome (BBS) gene BBS1 p.M390R variant in nonsyndromic autosomal recessive retinitis pigmentosa (RP).

Methods Homozygosity mapping of a patient with isolated RP was followed by BBS1 sequence analysis. We performed restriction fragment length polymorphism analysis of the p.M390R allele in 2007 patients with isolated RP or autosomal recessive RP and in 1824 ethnically matched controls. Patients with 2 BBS1 variants underwent extensive clinical and ophthalmologic assessment.

Results In an RP proband who did not fulfill the clinical criteria for BBS, we identified a large homozygous region encompassing the BBS1 gene, which carried the p.M390R variant. In addition, this variant was detected homozygously in 10 RP patients and 1 control, compound heterozygously in 3 patients, and heterozygously in 5 patients and 6 controls. The 14 patients with 2 BBS1 variants showed the entire clinical spectrum, from nonsyndromic RP to full-blown BBS. In 8 of 14 patients, visual acuity was significantly reduced. In patients with electroretinographic responses, a rod-cone pattern of photoreceptor degeneration was observed.

Conclusions Variants in BBS1 are significantly associated with nonsyndromic autosomal recessive RP and relatively mild forms of BBS. As exemplified in this study by the identification of a homozygous p.M390R variant in a control individual and in unaffected parents of BBS patients in other studies, cis - or trans -acting modifiers may influence the disease phenotype.

Clinical Relevance It is important to monitor patients with an early diagnosis of mild BBS phenotypes for possible life-threatening conditions.

Figures in this Article

Bardet-Biedl syndrome (BBS) (OMIM 209900) is a clinically and genetically heterogeneous disorder characterized by a wide spectrum of clinical features. It is considered a member of the group of conditions collectively called ciliopathies.1 Primary clinical features include retinitis pigmentosa (RP) (OMIM 268000), polydactyly, obesity, learning disabilities, hypogonadism in males, and renal abnormalities. Secondary clinical features include speech disorders, strabismus, brachydactyly or syndactyly, developmental delay, polydipsia-polyuria (diabetes insipidus), ataxia, mild spasticity, diabetes mellitus, dental crowding or hypodontia, congenital heart diseases, and hepatic fibrosis. The clinical diagnosis of BBS is based on the presence of at least 4 primary features or a combination of 3 primary plus at least 2 secondary features.2 The clinical phenotypic spectrum of BBS is wide, and genotype-phenotype correlations have not been clearly established.3,4 Some clinical features overlap those of other ciliopathies, such as McKusick-Kaufman (OMIM 604896), Alstrom (OMIM 203800), or Laurence-Moon (OMIM 245800) syndromes, which have been described in families with the BBS6, BBS10, or BBS12 mutation.57 The transmission of the disease is autosomal recessive,810 but a digenic inheritance in the form of triallelism has been reported in some families in which either 3 mutations in 2 BBS genes are required to manifest the phenotype11,12 or a third variant may modulate the expression of the clinical phenotype.1315

The prevalence of BBS ranges from 1:125 000 to 1:160 000 in Europe1618 and 1:65 000 in the Arab population19; a higher incidence was observed in isolated populations of Newfoundland (1:13 000),7 Kuwait (1:17 000),20 and the Faroe Islands (1:3700).21

To date, 15 genes have been associated with BBS.12,22 Most BBS proteins can be divided into 2 groups. One forms a complex called the BBSome (BBS1, BBS2, BBS4, BBS5, BBS7, BBS8, and BBS9), which is believed to recruit γ-glutamyl transpeptidase Rab8,23 and the second group comprises chaperoninlike proteins,24 including BBS6, BBS10, and BBS12. Mutations in known BBS genes are detected in approximately 75% of families, with BBS1 and BBS10 each accounting for 20% to 25% of families of European descent with BBS1 -associated disease.25,26 Two widespread mutations resulting from founder effects have been described, p.M390R in BBS18,13,27 and p.C91fsX95 in BBS10.26 The p.M390R variant is the most common BBS1 mutation and has been observed8,25 in approximately 80% of families with BBS1 -associated disease.

Retinitis pigmentosa is the most common inherited retinal degeneration, with an estimated worldwide prevalence of 1:4000,28 and is characterized by progressive photoreceptor dysfunction, followed by photoreceptor cell death. The disease is highly heterogeneous and displays all patterns of inheritance, that is, autosomal recessive, autosomal dominant, or X-linked. In addition, there are some cases with mitochondrial mutations and digenic inheritance.29,30 Mutations in 36 genes have been identified that cause autosomal recessive nonsyndromic RP, and mutations in 51 genes cause autosomal recessive syndromic retinal dystrophy, including BBS and Usher syndrome (RetNet, http://www.sph.uth.tmc.edu/RetNet/). These genes encode proteins involved in the phototransduction cascade, vitamin A metabolism, cellular or cytoskeletal structure, cell-to-cell signaling or synaptic interaction, gene expression, phagocytosis, and RNA splicing factors.30 Several RP proteins, including approximately half the BBS proteins, are part of the photoreceptor sensory cilium proteome, a large protein complex associated with and constituting the connecting cilium.31

Homozygosity mapping has proven to be fruitful to identify defects in known and newly identified genes implicated in autosomal recessive retinal degenerations3234 and to establish novel genotype-phenotype correlations.35,36 Using this approach, we identified a patient with RP with a large homozygous region encompassing the BBS1 gene. The fact that retinal degeneration is consistently seen in BBS patients with BBS1 mutations and previous observations that some mutations in BBS3 /ARL6, BBS8 /TTC8, BBS12, and BBS14 /CEP290 cause nonsyndromic retinal degeneration or retinal degeneration with minimal systemic features3740 prompted us to screen BBS1 in this patient and to further test the hypothesis that mutations in BBS1 are also a significant cause of nonsyndromic RP. In this study, we analyzed the p.M390R BBS1 mutation in 2007 patients with RP. We identified p.M390R BBS1 mutation in a homozygous or compound heterozygous manner in 14 patients with a wide clinical spectrum ranging from nonsyndromic RP to classic BBS, as well as in 1 putative healthy individual.

PATIENTS AND CLINICAL EVALUATION

In Canada, Europe, and Israel, 2007 unrelated patients with isolated or autosomal recessive RP (80 from Ghent, 96 from Jerusalem, 245 from Madrid, 361 from Montpellier, 343 from Montreal, 143 from Naples, 215 from Nijmegen, and 524 from Tübingen) and 1824 ethnically matched individuals serving as controls (103 from Ghent, 100 from Jerusalem, 320 from Madrid, 56 from Montpellier, 361 from Montreal, 140 from Naples, 233 from Nijmegen, and 511 from Tübingen) were included in the study. The diagnosis of RP was based on ophthalmologic examination that included measurement of best-corrected visual acuity, Goldmann visual fields, slitlamp biomicroscopy, dilated indirect ophthalmoscopy, and fundus photography. In addition, full-field flash electroretinography (ERG), according to the guidelines of the International Society of Clinical Electrophysiology of Vision,41 was performed when Goldmann visual fields were measurable and indicated a preserved visual field with peripheral limits beyond the pericentral 10°. A broad definition of RP was used to avoid excluding patients with atypical features: progressive visual loss, night blindness, and abnormal ERG findings in a rod-cone pattern when recordable. Blood samples were obtained after informed consent forms were signed. Ethics approval was given to all participating institutions, and the study conformed to the tenets of the Declaration of Helsinki. Participants were evaluated again after the identification of the BBS1 gene defects, since they had previously received a diagnosis of nonsyndromic RP. Special attention was given to identifying systemic features associated with BBS,2 which include the primary features of RP, polydactyly, obesity, learning disabilities, hypogonadism in males, and renal abnormalities, and the secondary features of speech disorders, cataract, brachydactyly or syndactyly, developmental delay, polydipsia/polyuria (diabetes insipidus), ataxia, mild spasticity, diabetes mellitus, dental crowding or hypodontia, congenital heart diseases, and hepatic fibrosis. Where and when appropriate, patients were clinically reexamined or their records were again reviewed. Clinical evaluation included best-corrected visual acuity and slitlamp biomicroscopy of the anterior segment and retina. Additional examinations included kinetic and/or static perimetry and ERG according to the protocol of the International Society for Clinical Electrophysiology of Vision.

HOMOZYGOSITY MAPPING AND BBS1 MUTATION ANALYSIS

Genomic DNAs were isolated from lymphocytes by standard salting-out procedures.42 Only the DNA sample of patient 5 was genotyped, using a microarray that contains 500 000 single-nucleotide polymorphisms (SNPs) (GeneChip Genome-Wide Human SNP Array 5.0; Affymetrix). Array experiments were performed according to protocols provided by the manufacturer. The 5.0 array data were genotyped (Genotype Console, version 2.1; Affymetrix) and, subsequently, regions of homozygosity were identified using commercial software (Partek, version 6.1, Partek, Inc).

Primers for the amplification of the 17 coding exons and splice junctions of BBS1 were designed by Primer343 and are available on request. Polymerase chain reaction (PCR) products were purified with 96-well filter plates (Multiscreen HTS-PCR; Millipore) or by gel extraction (Qia-Quick Gel Extraction Kit; Qiagen). Sequencing was performed with dye terminator chemistry (BigDye Terminator, version 3 on a 3100, 3730, or 3730XL DNA analyzer; Applied Biosystems, Inc).

SCREENING FOR THE BBS1 p.M390R AND MGC1203 C.403C>T VARIANTS

We developed a restriction enzyme test to screen the patients and controls for the recurrent BBS1 p.M390R mutation because the c.1169T>G variant in exon 12 introduces an Ava II recognition site (G/GWCC). The PCR analysis of exon 12 of BBS1 was performed with forward primer 5′-CCTGTCTTGCTTTCCTCTCC-3′ and reverse primer 5′-TCCTCCTCTTTCCCCAGAAG-3′, using 50 ng of DNA and 10 pmol of each primer in a standard 25-μL reaction. The PCR amplification was performed (PTC-200 Thermo Cycler; MJ Research) under the following conditions: 3 minutes at 94°C, 35 cycles at 94°C for 30 seconds, 58°C for 30 seconds, 72°C for 45 seconds, and a final extension step at 72°C for 10 minutes. The PCR products were purified with 96-well filter plates (Multiscreen HTS-PCR; Millipore). At that time, 10 μL of the PCR product was digested with 2 U of Ava II (New England Biolabs) in the appropriate buffer at 37°C for 2 hours, and the size was discriminated by agarose gel electrophoresis. After detecting the mutations, Sanger sequencing was performed to confirm the presence of the mutation.

The presence of the MGC1203 c.403C>T variant was tested in all patients with 2 BBS1 variants and in the control individual with BBS1 p.M390R in homozygosity. This was done by sequencing PCR products generated using forward primer 5′-ACTGGTGCATAGGCAGATGG-3′ and reverse primer 5′-CATGGACTGGGCCCTACAG-3′. The PCR products were purified with 96-well filter plates (Multiscreen HTS-PCR; Millipore). Sequencing was performed with dye terminator chemistry (BigDye Terminator, version 3 on a 3100, 3730, or 3730XL DNA analyzer; Applied Biosystems, Inc).

IN SILICO ASSESSMENT OF MISSENSE SUBSTITUTIONS

We used PolyPhen-244 (http://genetics.bwh.harvard.edu/pph2/index.shtml) and SIFT45 (http://sift.jcvi.org) to predict the functional effect of novel missense substitutions identified in this study. To assess the evolutionary conservation, amino acid sequences of orthologous BBS1 proteins (Pan troglodites XP_001171950.1, Sus scrofa NP_001091721, Canis lupus familiaris XP_540830.2, Mus musculus NP_001028300, Xenopus tropicalis NP_001116276.1, Drosophila melanogaster NP_648080.1, and Caenorhabditis elegans NP_740933.1) were obtained from the NCBI protein database (http://www.ncbi.nlm.nih.gov/protein/) and were aligned with the protein sequence of human BBS1 (NP_078925.3) using Vector NTI software (version 11; Invitrogen).

IDENTIFICATION OF BBS1 MUTATIONS IN RP PATIENTS

Upon homozygosity mapping, several homozygous regions were identified in patient 5, who received a diagnosis of severe RP, the largest of which measured 19 Mb and encompassed the BBS1 gene on chromosome 11q13.2. Sequence analysis of all 17 coding exons of BBS1 revealed the homozygous c.1169T>G (p.M390R) missense mutation in exon 12. To determine whether the p.M390R variant could be a rather frequent cause of nonsyndromic RP, we carried out a restriction fragment length polymorphism analysis for the p.M390R BBS1 mutation in 2006 patients with isolated or autosomal recessive RP in Canada, Europe, and Israel. We found 8 additional unrelated patients and a sibling pair with a homozygous p.M390R mutation (Table 1). Three patients carried the p.M390R allele combined with a second BBS1 variant in a compound heterozygous state. Two of these mutations (c.1163T>C [p.L388P] and c.803G>C [p.R268P], detected in patients 2 and 13, respectively) are novel, and 1 mutation (c.1130_1134del [p.C377WfsX36] in patient 4) was described previously.27 Alignment of the BBS1 amino acid sequences of various orthologs showed that the substituted amino acids (ie, leucine at position 388 and arginine at position 268) are highly conserved from human to C elegans. PolyPhen-2 predicted that p.L388P and p.R268P variants are probably damaging, and SIFT analysis revealed that neither is tolerated.

Table Graphic Jump LocationTable 1. Spectrum of Ocular and Extraocular Features of Patients With BBS1 Mutations

Analysis using restriction fragment length polymorphism revealed 5 patients with only 1 p.M390R variant; subsequent sequence analysis of the 17 BBS1 exons did not reveal a second allele. In 1824 ethnically matched control individuals, we found 6 heterozygous p.M390R carriers and 1 individual who was homozygous for this variant. Because these were anonymous healthy individuals, further clinical assessments could not be performed.

Because Badano et al14 identified a modifier allele for BBS in MGC1203, we tested the presence of the c.403C>T variant in all cases and the 1 control individual with 2 BBS1 alleles. Using restriction fragment length polymorphism analysis, this modifier allele was not detected in any of these cases.

CLINICAL FINDINGS

The clinical findings of the 14 patients with BBS1 variants are reported in Table 1. Patients were divided into 4 groups. Group A contained the 3 patients who appeared to have a nonsyndromic form of RP. In these patients, cataract was the only feature that might be related to BBS. Group B consisted of 4 patients who may have a nonsyndromic form of RP. These patients showed few extraocular features that may be associated with the retinal phenotype. Three of these patients were obese, and, in 1 patient, routine ultrasound revealed a few mild renal cysts without renal dysfunction. The 6 patients in group C demonstrated definite extraocular features commonly associated with BBS but insufficient to warrant a diagnosis of classic BBS. Finally, group D included 1 patient who fulfilled the criteria for the diagnosis of classic BBS after reevaluation.

The results of the ophthalmologic examinations of the 14 patients with RP or (mild) BBS are summarized in Table 2. In most patients, night blindness was the first symptom of retinal degeneration. Early photoreceptor dysfunction, at or before the age of 10 years, was observed in 6 of the 14 patients (including 2 siblings, patients 3 and 7). A visual acuity level of counting fingers or less was observed in 8 patients, and none of the patients displayed visual acuity better than 20/40. Figure 1 (patient 4) clearly illustrates the severity of the phenotype in these patients. A relatively later age at onset did not necessarily reflect positively on the chance of encountering severe visual loss, as demonstrated by patient 14, who experienced visual field loss at age 35 years, but at age 54 years, her visual acuity was reduced to light perception. In most patients there was extensive loss of the visual field. Four patients could not see the largest target or showed only a modest temporal region of remaining sensitivity; 6 patients demonstrated severe visual field constriction. When ERG responses could be elicited, a rod-cone pattern of photoreceptor degeneration was observed. In 10 of 13 patients, the ERG became nonrecordable during the course of their disease.

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Figure 1. The right eye of patient 4 at age 33 years. This color fundus photograph illustrates the severity of the retinitis pigmentosa phenotype in many of the patients in this study. In addition to the midperipheral bone spicules and attenuated vessels, there is widespread chorioretinal atrophy. The atrophy is especially severe at the posterior pole. The visual acuity in this patient was only light perception; electroretinographic responses were absent.

Table Graphic Jump LocationTable 2. Ocular Findings in Patients With BBS1 Mutations

Mutations in the BBS1 gene have been associated with BBS,27 and in one study46 they were associated with RP and variable mild systemic features. For some BBS families, a digenic-triallelic inheritance model has been proposed in which interactions were suggested between BBS1 and BBS2 or BBS1 and BBS6,1315 although this has not been replicated in other studies.810 We found that the BBS1 variant p.M390R is significantly associated with nonsyndromic RP or mild BBS because we identified it in 21 of 4014 alleles in our probands vs 8 of 3648 alleles in the controls (P = .02, Fisher exact test). Similarly, the BBS3 /ARL6 variant p.A89V and the BBS12 variant p.S701X have been implicated in both nonsyndromic RP and BBS.40,47 A splice mutation affecting a retina-specific exon of BBS8 /TTC8 also causes nonsyndromic RP.48 In other studies,4951 considerable variations of systemic features have been described in patients with BBS.

The phenotype of the BBS1 -associated retinal dystrophy in our patient group was more severe than that reported by Azari and coworkers.52 Eight of the 14 patients in the current study had visual acuity of counting fingers or lower, whereas Azari and coworkers observed only 1 patient with visual acuity below 20/200 in their 10 patients with principally classic BBS. In addition, the age at onset was relatively early in our patients and nystagmus was present in 3 patients. For the most part, the patients in the current study showed classic RP with a relatively homogeneous clinical presentation. In view of the early age at onset, low visual acuity, and extensive visual field loss, the photoreceptor dystrophy of the 14 patients in this study should be considered severe.

The disease spectrum of the patients in this study is broad, and any attempt at organization is arbitrary at best. Cataract is commonly found in up to 50% of patients with RP and, in many patients, cataract surgery is performed at a relative early age.5355 Consequently, in the absence of other primary or secondary signs, we believed that the condition in the 3 patients in group A should be diagnosed as nonsyndromic RP, despite the presence of the secondary feature cataract. The same line of reasoning more or less holds with the primary feature of obesity in the patients in group B. Obesity is a rather nonspecific finding in current Western society and perhaps even more so in patients with retinal degeneration who are prone to physical inactivity.56 In addition to RP, the patients in group B had few primary and/or secondary features that could be associated with BBS but may be coincidental. The isolated presence of moderate obesity, especially without truncal distribution and in combination with parental obesity, is not necessarily an indication of extraocular abnormalities due to BBS1 mutations, so that nonsyndromic RP is at least a possibility. Following this approach, 3 of our 14 patients (group A) exhibited nonsyndromic RP and 4 patients (group B) demonstrated a form of RP that may be nonsyndromic.

Despite the inclusion criterion of autosomal recessive and/or isolated RP, 7 patients showed syndromic features that seem to be associated with the retinal phenotype. In one patient (group D), a previously undiagnosed classic form of BBS was discovered. The extra digits were removed shortly after birth in this patient, emphasizing the importance of obtaining a complete history in patients with RP. In the remaining 6 patients (group C), extraocular features were present, but these abnormalities were insufficient to warrant the diagnosis of classic BBS. Extraocular features in these 6 patients were highly divergent, making correct identification of this milder form of BBS challenging. In patient 11, RP was associated with nephronophthisis, a combination known as the Senior-Løken syndrome. This syndrome has been associated with mutations in the nephronophthisis genes and not, to our knowledge, with BBS1 mutations. The observation that BBS1 mutations may cause milder BBS phenotypes has been reported in a case history of 2 brothers.46 The danger of a misdiagnosis in patients with milder BBS phenotypes is important in view of the potentially severe consequences of life-threatening conditions associated with BBS1 mutations, as well as the accuracy of genetic counseling.

The presence of a presumed unaffected individual with 2 p.M390R variants in our study is not unprecedented; Badano and coworkers13 reported on 2 families with 2 p.M390R alleles in BBS patients and their unaffected fathers. The differential penetrance of BBS1 alleles in one of these families was subsequently explained by the detection of a heterozygous trans -acting epistatic allele (MGC1203 ; c.430C>T) in the patient with BBS but not in the unaffected father.14 The MGC1203 gene encodes a pericentriolar protein that interacts with BBS1, BBS2, BBS4, BBS5, BBS6, BBS7, and BBS8 and colocalizes with BBS1 and BBS4. The MGC1203 variant c.430C>T enhances the use of a cryptic splice acceptor site, causing the introduction of a premature stop codon and the reduction of MGC1203 mRNA levels. An alternative explanation for the variable phenotypes associated with BBS1 alleles could be cis- acting regulators of expression. We did not find this modifier in our case and control patients with 2 BBS1 alleles. Different enhancer or promoter variants may result in higher messenger RNA expression levels of the BBS1 p.M390R alleles in unaffected individuals, which may compensate for the reduced activity of the p.M390R-carrying BBS1 protein (Figure 2A, cis -acting modifier). Alternatively, as shown in Figure 2B, mild BBS or BBS can also be caused by a combination of 2 BBS1 variants and a negatively acting trans -acting modifier, such as the MGC1203 variant c.430C>T.

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Figure 2.Cis- and trans- acting Bardet-Biedl syndrome (BBS) gene BBS1 expression regulator model. A, Enhancer/promoter variants (cis -acting) may modulate the messenger RNA expression levels of BBS1 and thereby determine the penetrance or expression of disease. Unaffected individuals carry hypomorphic variants (v1 and v2, such as the p.M390R variant) on 1 or 2 highly (+++) expressed BBS1 alleles; moderately (++) expressed BBS1 alleles result in nonsyndromic retinitis pigmentosa (RP) or mild BBS, and low (+/−) expressed BBS1 alleles result in BBS. B, A trans -acting third variant (v3) present in an interactor of BBS1 or a transcription factor negatively regulating the expression of BBS1 may contribute to the phenotype.

In conclusion, by analyzing a very large cohort of patients with isolated or autosomal recessive RP, we identified BBS1 variants in individuals with a wide clinical spectrum, ranging from nonsyndromic RP (mild BBS) to classic BBS.

Correspondence: B. Jeroen Klevering, MD, PhD, Department of Ophthalmology, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB, Nijmegen, the Netherlands (b.klevering@ohk.umcn.nl).

Submitted for Publication: June 16, 2011; final revision received April 23, 2012; accepted June 6, 2012.

Author Contributions: Drs Cremers and Klevering contributed equally to this manuscript.

Conflict of Interest Disclosures: None reported.

Funding/Support: These studies were supported by the Radboud University Nijmegen Medical Centre (Drs den Hollander and Cremers); grant BR-GE-0510-0489-RAD from the Foundation Fighting Blindness US (Dr den Hollander); the Algemene Nederlandse Vereniging ter Voorkoming van Blindheid, Gelderse Blinden Stichting, Landelijke Stichting voor Blinden en Slechtzienden, Retina Nederland, Stichting Oogfonds Nederland, Stichting Wetenschappelijk Onderzoek het Oogziekenhuis, the Rotterdamse Vereniging Blindenbelangen, the Stichting AF Deutman Researchfonds Oogheelkunde (Drs den Hollander and Cremers); the Foundation Fighting Blindness Canada, Canadian Institute of Health Research, Fond de la recherche en santé du Québec, Reseau Vision, and National Intitutes of Health (Dr Koenekoop); Organización Nacional de Ciegos, FIS PS09/00459, and CIBERER (ISCIII) (Dr Ayuso); the Italian Telethon Foundation, the Italian Ministry of Health (Dr Banfi); and grant KAN 1524611N from the Research Foundation–Flanders/FWO (Drs De Baere and Leroy). Drs De Baere and Leroy are Senior Clinical Investigators of the Research Foundation–Flanders, Belgium, and are further supported by Research Foundation–Flanders grants 3E000203, 31509107, and 31518209 (Dr De Baere) and OZP 3G004306 (Drs Banin and Leroy).

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Zaghloul NA, Katsanis N. Mechanistic insights into Bardet-Biedl syndrome, a model ciliopathy.  J Clin Invest. 2009;119(3):428-437
PubMed   |  Link to Article
Badano JL, Kim JC, Hoskins BE,  et al.  Heterozygous mutations in BBS1, BBS2 and BBS6 have a potential epistatic effect on Bardet-Biedl patients with two mutations at a second BBS locus.  Hum Mol Genet. 2003;12(14):1651-1659
PubMed   |  Link to Article
Badano JL, Leitch CC, Ansley SJ,  et al.  Dissection of epistasis in oligogenic Bardet-Biedl syndrome.  Nature. 2006;439(7074):326-330
PubMed   |  Link to Article
Khanna H, Davis EE, Murga-Zamalloa CA,  et al.  A common allele in RPGRIP1L is a modifier of retinal degeneration in ciliopathies.  Nat Genet. 2009;41(6):739-745
PubMed   |  Link to Article
Beales PL, Warner AM, Hitman GA, Thakker R, Flinter FA. Bardet-Biedl syndrome: a molecular and phenotypic study of 18 families.  J Med Genet. 1997;34(2):92-98
PubMed   |  Link to Article
Haim M. Prevalence of retinitis pigmentosa and allied disorders in Denmark, III: hereditary pattern.  Acta Ophthalmol (Copenh). 1992;70(5):615-624
PubMed   |  Link to Article
Klein D, Ammann F. The syndrome of Laurence-Moon-Bardet-Biedl and allied diseases in Switzerland: clinical, genetic and epidemiological studies.  J Neurol Sci. 1969;9(3):479-513
PubMed   |  Link to Article
Farag TI, Teebi AS. Bardet-Biedl and Laurence-Moon syndromes in a mixed Arab population.  Clin Genet. 1988;33(2):78-82
PubMed   |  Link to Article
Teebi AS. Autosomal recessive disorders among Arabs: an overview from Kuwait.  J Med Genet. 1994;31(3):224-233
PubMed   |  Link to Article
Hjortshøj TD, Grønskov K, Brøndum-Nielsen K, Rosenberg T. A novel founder BBS1 mutation explains a unique high prevalence of Bardet-Biedl syndrome in the Faroe Islands.  Br J Ophthalmol. 2009;93(3):409-413
PubMed   |  Link to Article
Kim SK, Shindo A, Park TJ,  et al.  Planar cell polarity acts through septins to control collective cell movement and ciliogenesis.  Science. 2010;329(5997):1337-1340
PubMed   |  Link to Article
Nachury MV, Loktev AV, Zhang Q,  et al.  A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis.  Cell. 2007;129(6):1201-1213
PubMed   |  Link to Article
Stoetzel C, Muller J, Laurier V,  et al.  Identification of a novel BBS gene (BBS12) highlights the major role of a vertebrate-specific branch of chaperonin-related proteins in Bardet-Biedl syndrome.  Am J Hum Genet. 2007;80(1):1-11
PubMed   |  Link to Article
Beales PL, Badano JL, Ross AJ,  et al.  Genetic interaction of BBS1 mutations with alleles at other BBS loci can result in non-mendelian Bardet-Biedl syndrome.  Am J Hum Genet. 2003;72(5):1187-1199
PubMed   |  Link to Article
Stoetzel C, Laurier V, Davis EE,  et al.  BBS10 encodes a vertebrate-specific chaperonin-like protein and is a major BBS locus.  Nat Genet. 2006;38(5):521-524
PubMed   |  Link to Article
Mykytyn K, Nishimura DY, Searby CC,  et al.  Identification of the gene (BBS1) most commonly involved in Bardet-Biedl syndrome, a complex human obesity syndrome.  Nat Genet. 2002;31(4):435-438
PubMed
Haim M. The epidemiology of retinitis pigmentosa in Denmark.  Acta Ophthalmol Scand. 2002;80:(suppl 233)  1-34Link to Article
Link to Article
Daiger SP, Bowne SJ, Sullivan LS. Perspective on genes and mutations causing retinitis pigmentosa.  Arch Ophthalmol. 2007;125(2):151-158
PubMed   |  Link to Article
Berger W, Kloeckener-Gruissem B, Neidhardt J. The molecular basis of human retinal and vitreoretinal diseases.  Prog Retin Eye Res. 2010;29(5):335-375
PubMed   |  Link to Article
Liu Q, Tan G, Levenkova N,  et al.  The proteome of the mouse photoreceptor sensory cilium complex.  Mol Cell Proteomics. 2007;6(8):1299-1317
PubMed   |  Link to Article
Collin RWJ, Littink KW, Klevering BJ,  et al.  Identification of a 2 Mb human ortholog of Drosophila eyes shut/spacemaker that is mutated in patients with retinitis pigmentosa.  Am J Hum Genet. 2008;83(5):594-603
PubMed   |  Link to Article
Collin RWJ, van den Born LI, Klevering BJ,  et al.  High-resolution homozygosity mapping is a powerful tool to detect novel mutations causative of autosomal recessive RP in the Dutch population.  Invest Ophthalmol Vis Sci. 2011;52(5):2227-2239
PubMed   |  Link to Article
Bandah-Rozenfeld D, Collin RWJ, Banin E,  et al.  Mutations in IMPG2, encoding interphotoreceptor matrix proteoglycan 2, cause autosomal-recessive retinitis pigmentosa.  Am J Hum Genet. 2010;87(2):199-208
PubMed   |  Link to Article
Estrada-Cuzcano A, Koenekoop RK, Coppieters F,  et al.  IQCB1 mutations in patients with Leber congenital amaurosis.  Invest Ophthalmol Vis Sci. 2011;52(2):834-839
PubMed   |  Link to Article
Khan MI, Kersten FFM, Azam M,  et al.  CLRN1 mutations cause nonsyndromic retinitis pigmentosa.  Ophthalmology. 2011;118(7):1444-1448
PubMed
Abu Safieh L, Aldahmesh MA, Shamseldin H,  et al.  Clinical and molecular characterisation of Bardet-Biedl syndrome in consanguineous populations: the power of homozygosity mapping.  J Med Genet. 2010;47(4):236-241
PubMed   |  Link to Article
Aldahmesh MA, Safieh LA, Alkuraya H,  et al.  Molecular characterization of retinitis pigmentosa in Saudi Arabia.  Mol Vis. 2009;15:2464-2469
PubMed
den Hollander AI, Koenekoop RKK, Yzer S,  et al.  Mutations in the CEP290 (NPHP6) gene are a frequent cause of Leber congenital amaurosis.  Am J Hum Genet. 2006;79(3):556-561
PubMed   |  Link to Article
Pawlik B, Mir A, Iqbal H,  et al.  A novel familial BBS12 mutation associated with a mild phenotype: implications for clinical and molecular diagnostic strategies.  Mol Syndromol. 2010;1(1):27-34
PubMed   |  Link to Article
Marmor MF, Fulton AB, Holder GE, Miyake Y, Brigell M, Bach M.International Society for Clinical Electrophysiology of Vision.  ISCEV standard for full-field clinical electroretinography (2008 update).  Doc Ophthalmol. 2009;118(1):69-77
PubMed   |  Link to Article
Aldred MA, Teague PW, Jay M,  et al.  Retinitis pigmentosa families showing apparent X linked inheritance but unlinked to the RP2 or RP3 loci.  J Med Genet. 1994;31(11):848-852
PubMed   |  Link to Article
Rozen S, Skaletsky H. Primer3 on the WWW for general users and for biologist programmers.  Methods Mol Biol. 2000;132:365-386
PubMed
Adzhubei IA, Schmidt S, Peshkin L,  et al.  A method and server for predicting damaging missense mutations.  Nat Methods. 2010;7(4):248-249
PubMed   |  Link to Article
Ng PC, Henikoff S. Predicting deleterious amino acid substitutions.  Genome Res. 2001;11(5):863-874
PubMed   |  Link to Article
Cannon PS, Clayton-Smith J, Beales PL, Lloyd IC. Bardet-Biedl syndrome: an atypical phenotype in brothers with a proven BBS1 mutation.  Ophthalmic Genet. 2008;29(3):128-132
PubMed   |  Link to Article
Pretorius PR, Aldahmesh MA, Alkuraya FS, Sheffield VC, Slusarski DC. Functional analysis of BBS3 A89V that results in non-syndromic retinal degeneration.  Hum Mol Genet. 2011;20(8):1625-1632
PubMed   |  Link to Article
Riazuddin SA, Iqbal M, Wang Y,  et al.  A splice-site mutation in a retina-specific exon of BBS8 causes nonsyndromic retinitis pigmentosa.  Am J Hum Genet. 2010;86(5):805-812
PubMed   |  Link to Article
Bruford EA, Riise R, Teague PW,  et al.  Linkage mapping in 29 Bardet-Biedl syndrome families confirms loci in chromosomal regions 11q13, 15q22.3-q23, and 16q21.  Genomics. 1997;41(1):93-99
PubMed   |  Link to Article
Carmi R, Elbedour K, Stone EM, Sheffield VC. Phenotypic differences among patients with Bardet-Biedl syndrome linked to three different chromosome loci.  Am J Med Genet. 1995;59(2):199-203
PubMed   |  Link to Article
Riise R, Andréasson S, Borgaström MK,  et al.  Intrafamilial variation of the phenotype in Bardet-Biedl syndrome.  Br J Ophthalmol. 1997;81(5):378-385
PubMed   |  Link to Article
Azari AA, Aleman TS, Cideciyan AV,  et al.  Retinal disease expression in Bardet-Biedl syndrome-1 (BBS1) is a spectrum from maculopathy to retina-wide degeneration.  Invest Ophthalmol Vis Sci. 2006;47(11):5004-5010
PubMed   |  Link to Article
Pruett RC. Retinitis pigmentosa: clinical observations and correlations.  Trans Am Ophthalmol Soc. 1983;81:693-735
PubMed
Hamel C. Retinitis pigmentosa.  Orphanet J Rare Dis. 2006;1:40
PubMed  |  Link to Article   |  Link to Article
Lee SH, Yu HG, Seo JM,  et al.  Hereditary and clinical features of retinitis pigmentosa in Koreans.  J Korean Med Sci. 2010;25(6):918-923
PubMed   |  Link to Article
Pietiläinen KH, Kaprio J, Borg P,  et al.  Physical inactivity and obesity: a vicious circle.  Obesity (Silver Spring). 2008;16(2):409-414
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Graphic Jump Location

Figure 1. The right eye of patient 4 at age 33 years. This color fundus photograph illustrates the severity of the retinitis pigmentosa phenotype in many of the patients in this study. In addition to the midperipheral bone spicules and attenuated vessels, there is widespread chorioretinal atrophy. The atrophy is especially severe at the posterior pole. The visual acuity in this patient was only light perception; electroretinographic responses were absent.

Place holder to copy figure label and caption
Graphic Jump Location

Figure 2.Cis- and trans- acting Bardet-Biedl syndrome (BBS) gene BBS1 expression regulator model. A, Enhancer/promoter variants (cis -acting) may modulate the messenger RNA expression levels of BBS1 and thereby determine the penetrance or expression of disease. Unaffected individuals carry hypomorphic variants (v1 and v2, such as the p.M390R variant) on 1 or 2 highly (+++) expressed BBS1 alleles; moderately (++) expressed BBS1 alleles result in nonsyndromic retinitis pigmentosa (RP) or mild BBS, and low (+/−) expressed BBS1 alleles result in BBS. B, A trans -acting third variant (v3) present in an interactor of BBS1 or a transcription factor negatively regulating the expression of BBS1 may contribute to the phenotype.

Tables

Table Graphic Jump LocationTable 1. Spectrum of Ocular and Extraocular Features of Patients With BBS1 Mutations
Table Graphic Jump LocationTable 2. Ocular Findings in Patients With BBS1 Mutations

References

Badano JL, Mitsuma N, Beales PL, Katsanis N. The ciliopathies: an emerging class of human genetic disorders.  Annu Rev Genomics Hum Genet. 2006;7:125-148
PubMed   |  Link to Article
Beales PL, Elcioglu N, Woolf AS, Parker D, Flinter FA. New criteria for improved diagnosis of Bardet-Biedl syndrome: results of a population survey.  J Med Genet. 1999;36(6):437-446
PubMed
Deveault C, Billingsley G, Duncan JL,  et al.  BBS genotype-phenotype assessment of a multiethnic patient cohort calls for a revision of the disease definition.  Hum Mutat. 2011;32(6):610-619
PubMed   |  Link to Article
Janssen S, Ramaswami G, Davis EE,  et al.  Mutation analysis in Bardet-Biedl syndrome by DNA pooling and massively parallel resequencing in 105 individuals.  Hum Genet. 2011;129(1):79-90
PubMed   |  Link to Article
Billingsley G, Bin J, Fieggen KJ,  et al.  Mutations in chaperonin-like BBS genes are a major contributor to disease development in a multiethnic Bardet-Biedl syndrome patient population.  J Med Genet. 2010;47(7):453-463
PubMed   |  Link to Article
Moore SJ, Green JS, Fan YL,  et al.  Clinical and genetic epidemiology of Bardet-Biedl syndrome in Newfoundland: a 22-year prospective, population-based, cohort study.  Am J Med Genet A. 2005;132(4):352-360
PubMed
Schaefer E, Durand M, Stoetzel C,  et al.  Molecular diagnosis reveals genetic heterogeneity for the overlapping MKKS and BBS phenotypes.  Eur J Med Genet. 2011;54(2):157-160
PubMed   |  Link to Article
Mykytyn K, Nishimura DY, Searby CC,  et al.  Evaluation of complex inheritance involving the most common Bardet-Biedl syndrome locus (BBS1).  Am J Hum Genet. 2003;72(2):429-437
PubMed   |  Link to Article
Smaoui N, Chaabouni M, Sergeev YV,  et al.  Screening of the eight BBS genes in Tunisian families: no evidence of triallelism.  Invest Ophthalmol Vis Sci. 2006;47(8):3487-3495
PubMed   |  Link to Article
Hichri H, Stoetzel C, Laurier V,  et al.  Testing for triallelism: analysis of six BBS genes in a Bardet-Biedl syndrome family cohort.  Eur J Hum Genet. 2005;13(5):607-616
PubMed   |  Link to Article
Katsanis N, Ansley SJ, Badano JL,  et al.  Triallelic inheritance in Bardet-Biedl syndrome, a mendelian recessive disorder.  Science. 2001;293(5538):2256-2259
PubMed   |  Link to Article
Zaghloul NA, Katsanis N. Mechanistic insights into Bardet-Biedl syndrome, a model ciliopathy.  J Clin Invest. 2009;119(3):428-437
PubMed   |  Link to Article
Badano JL, Kim JC, Hoskins BE,  et al.  Heterozygous mutations in BBS1, BBS2 and BBS6 have a potential epistatic effect on Bardet-Biedl patients with two mutations at a second BBS locus.  Hum Mol Genet. 2003;12(14):1651-1659
PubMed   |  Link to Article
Badano JL, Leitch CC, Ansley SJ,  et al.  Dissection of epistasis in oligogenic Bardet-Biedl syndrome.  Nature. 2006;439(7074):326-330
PubMed   |  Link to Article
Khanna H, Davis EE, Murga-Zamalloa CA,  et al.  A common allele in RPGRIP1L is a modifier of retinal degeneration in ciliopathies.  Nat Genet. 2009;41(6):739-745
PubMed   |  Link to Article
Beales PL, Warner AM, Hitman GA, Thakker R, Flinter FA. Bardet-Biedl syndrome: a molecular and phenotypic study of 18 families.  J Med Genet. 1997;34(2):92-98
PubMed   |  Link to Article
Haim M. Prevalence of retinitis pigmentosa and allied disorders in Denmark, III: hereditary pattern.  Acta Ophthalmol (Copenh). 1992;70(5):615-624
PubMed   |  Link to Article
Klein D, Ammann F. The syndrome of Laurence-Moon-Bardet-Biedl and allied diseases in Switzerland: clinical, genetic and epidemiological studies.  J Neurol Sci. 1969;9(3):479-513
PubMed   |  Link to Article
Farag TI, Teebi AS. Bardet-Biedl and Laurence-Moon syndromes in a mixed Arab population.  Clin Genet. 1988;33(2):78-82
PubMed   |  Link to Article
Teebi AS. Autosomal recessive disorders among Arabs: an overview from Kuwait.  J Med Genet. 1994;31(3):224-233
PubMed   |  Link to Article
Hjortshøj TD, Grønskov K, Brøndum-Nielsen K, Rosenberg T. A novel founder BBS1 mutation explains a unique high prevalence of Bardet-Biedl syndrome in the Faroe Islands.  Br J Ophthalmol. 2009;93(3):409-413
PubMed   |  Link to Article
Kim SK, Shindo A, Park TJ,  et al.  Planar cell polarity acts through septins to control collective cell movement and ciliogenesis.  Science. 2010;329(5997):1337-1340
PubMed   |  Link to Article
Nachury MV, Loktev AV, Zhang Q,  et al.  A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis.  Cell. 2007;129(6):1201-1213
PubMed   |  Link to Article
Stoetzel C, Muller J, Laurier V,  et al.  Identification of a novel BBS gene (BBS12) highlights the major role of a vertebrate-specific branch of chaperonin-related proteins in Bardet-Biedl syndrome.  Am J Hum Genet. 2007;80(1):1-11
PubMed   |  Link to Article
Beales PL, Badano JL, Ross AJ,  et al.  Genetic interaction of BBS1 mutations with alleles at other BBS loci can result in non-mendelian Bardet-Biedl syndrome.  Am J Hum Genet. 2003;72(5):1187-1199
PubMed   |  Link to Article
Stoetzel C, Laurier V, Davis EE,  et al.  BBS10 encodes a vertebrate-specific chaperonin-like protein and is a major BBS locus.  Nat Genet. 2006;38(5):521-524
PubMed   |  Link to Article
Mykytyn K, Nishimura DY, Searby CC,  et al.  Identification of the gene (BBS1) most commonly involved in Bardet-Biedl syndrome, a complex human obesity syndrome.  Nat Genet. 2002;31(4):435-438
PubMed
Haim M. The epidemiology of retinitis pigmentosa in Denmark.  Acta Ophthalmol Scand. 2002;80:(suppl 233)  1-34Link to Article
Link to Article
Daiger SP, Bowne SJ, Sullivan LS. Perspective on genes and mutations causing retinitis pigmentosa.  Arch Ophthalmol. 2007;125(2):151-158
PubMed   |  Link to Article
Berger W, Kloeckener-Gruissem B, Neidhardt J. The molecular basis of human retinal and vitreoretinal diseases.  Prog Retin Eye Res. 2010;29(5):335-375
PubMed   |  Link to Article
Liu Q, Tan G, Levenkova N,  et al.  The proteome of the mouse photoreceptor sensory cilium complex.  Mol Cell Proteomics. 2007;6(8):1299-1317
PubMed   |  Link to Article
Collin RWJ, Littink KW, Klevering BJ,  et al.  Identification of a 2 Mb human ortholog of Drosophila eyes shut/spacemaker that is mutated in patients with retinitis pigmentosa.  Am J Hum Genet. 2008;83(5):594-603
PubMed   |  Link to Article
Collin RWJ, van den Born LI, Klevering BJ,  et al.  High-resolution homozygosity mapping is a powerful tool to detect novel mutations causative of autosomal recessive RP in the Dutch population.  Invest Ophthalmol Vis Sci. 2011;52(5):2227-2239
PubMed   |  Link to Article
Bandah-Rozenfeld D, Collin RWJ, Banin E,  et al.  Mutations in IMPG2, encoding interphotoreceptor matrix proteoglycan 2, cause autosomal-recessive retinitis pigmentosa.  Am J Hum Genet. 2010;87(2):199-208
PubMed   |  Link to Article
Estrada-Cuzcano A, Koenekoop RK, Coppieters F,  et al.  IQCB1 mutations in patients with Leber congenital amaurosis.  Invest Ophthalmol Vis Sci. 2011;52(2):834-839
PubMed   |  Link to Article
Khan MI, Kersten FFM, Azam M,  et al.  CLRN1 mutations cause nonsyndromic retinitis pigmentosa.  Ophthalmology. 2011;118(7):1444-1448
PubMed
Abu Safieh L, Aldahmesh MA, Shamseldin H,  et al.  Clinical and molecular characterisation of Bardet-Biedl syndrome in consanguineous populations: the power of homozygosity mapping.  J Med Genet. 2010;47(4):236-241
PubMed   |  Link to Article
Aldahmesh MA, Safieh LA, Alkuraya H,  et al.  Molecular characterization of retinitis pigmentosa in Saudi Arabia.  Mol Vis. 2009;15:2464-2469
PubMed
den Hollander AI, Koenekoop RKK, Yzer S,  et al.  Mutations in the CEP290 (NPHP6) gene are a frequent cause of Leber congenital amaurosis.  Am J Hum Genet. 2006;79(3):556-561
PubMed   |  Link to Article
Pawlik B, Mir A, Iqbal H,  et al.  A novel familial BBS12 mutation associated with a mild phenotype: implications for clinical and molecular diagnostic strategies.  Mol Syndromol. 2010;1(1):27-34
PubMed   |  Link to Article
Marmor MF, Fulton AB, Holder GE, Miyake Y, Brigell M, Bach M.International Society for Clinical Electrophysiology of Vision.  ISCEV standard for full-field clinical electroretinography (2008 update).  Doc Ophthalmol. 2009;118(1):69-77
PubMed   |  Link to Article
Aldred MA, Teague PW, Jay M,  et al.  Retinitis pigmentosa families showing apparent X linked inheritance but unlinked to the RP2 or RP3 loci.  J Med Genet. 1994;31(11):848-852
PubMed   |  Link to Article
Rozen S, Skaletsky H. Primer3 on the WWW for general users and for biologist programmers.  Methods Mol Biol. 2000;132:365-386
PubMed
Adzhubei IA, Schmidt S, Peshkin L,  et al.  A method and server for predicting damaging missense mutations.  Nat Methods. 2010;7(4):248-249
PubMed   |  Link to Article
Ng PC, Henikoff S. Predicting deleterious amino acid substitutions.  Genome Res. 2001;11(5):863-874
PubMed   |  Link to Article
Cannon PS, Clayton-Smith J, Beales PL, Lloyd IC. Bardet-Biedl syndrome: an atypical phenotype in brothers with a proven BBS1 mutation.  Ophthalmic Genet. 2008;29(3):128-132
PubMed   |  Link to Article
Pretorius PR, Aldahmesh MA, Alkuraya FS, Sheffield VC, Slusarski DC. Functional analysis of BBS3 A89V that results in non-syndromic retinal degeneration.  Hum Mol Genet. 2011;20(8):1625-1632
PubMed   |  Link to Article
Riazuddin SA, Iqbal M, Wang Y,  et al.  A splice-site mutation in a retina-specific exon of BBS8 causes nonsyndromic retinitis pigmentosa.  Am J Hum Genet. 2010;86(5):805-812
PubMed   |  Link to Article
Bruford EA, Riise R, Teague PW,  et al.  Linkage mapping in 29 Bardet-Biedl syndrome families confirms loci in chromosomal regions 11q13, 15q22.3-q23, and 16q21.  Genomics. 1997;41(1):93-99
PubMed   |  Link to Article
Carmi R, Elbedour K, Stone EM, Sheffield VC. Phenotypic differences among patients with Bardet-Biedl syndrome linked to three different chromosome loci.  Am J Med Genet. 1995;59(2):199-203
PubMed   |  Link to Article
Riise R, Andréasson S, Borgaström MK,  et al.  Intrafamilial variation of the phenotype in Bardet-Biedl syndrome.  Br J Ophthalmol. 1997;81(5):378-385
PubMed   |  Link to Article
Azari AA, Aleman TS, Cideciyan AV,  et al.  Retinal disease expression in Bardet-Biedl syndrome-1 (BBS1) is a spectrum from maculopathy to retina-wide degeneration.  Invest Ophthalmol Vis Sci. 2006;47(11):5004-5010
PubMed   |  Link to Article
Pruett RC. Retinitis pigmentosa: clinical observations and correlations.  Trans Am Ophthalmol Soc. 1983;81:693-735
PubMed
Hamel C. Retinitis pigmentosa.  Orphanet J Rare Dis. 2006;1:40
PubMed  |  Link to Article   |  Link to Article
Lee SH, Yu HG, Seo JM,  et al.  Hereditary and clinical features of retinitis pigmentosa in Koreans.  J Korean Med Sci. 2010;25(6):918-923
PubMed   |  Link to Article
Pietiläinen KH, Kaprio J, Borg P,  et al.  Physical inactivity and obesity: a vicious circle.  Obesity (Silver Spring). 2008;16(2):409-414
PubMed   |  Link to Article

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