0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Research Letters |

Novel Compound Heterozygous Mutations in CERKL Cause Autosomal Recessive Retinitis Pigmentosa in a Nonconsanguineous Chinese Family FREE

Zhaohui Tang, MS; Zhaoxiang Wang, MD; Zhi Wang, MD; Tie Ke, PhD; Qing Kenneth Wang, PhD; Mugen Liu, PhD
Arch Ophthalmol. 2009;127(8):1077-1078. doi:10.1001/archophthalmol.2009.207.
Text Size: A A A
Published online

Retinitis pigmentosa (RP) (OMIM 268000) is characterized by night blindness, progressive constriction of the visual fields, and fundus changes, including bony spicule pigmentation. To date, a number of RP loci or genes have been reported.1 One of the autosomal recessive RP (arRP) loci, RP26, was mapped to chromosome 2q31-q33 in 1998. The disease-causing gene at this locus has been recently identified as the CERKL gene (ceramide kinase–like) (GenBank NM_201548), encoding a 532–amino acid protein that shares 29% identity with ceramide kinase.2,3 Only 3 CERKL mutations have been reported, including p.E257X in Spanish families,2,4 p.P106S in a consanguineous Pakistani family,5 and a splicing mutation in Yemeni Jewish families.6 We now report 2 novel compound heterozygous mutations in CERKL, c.156_157insT and c.758delT, which were found in a nonconsanguineous Chinese family with arRP. Our data indicate that compound heterozygous mutations of CERKL can cause RP.

A family with arRP was enrolled in a study in China and diagnosed by clinical and ophthalmological examinations. Peripheral blood was collected and genomic DNA was isolated. Linkage and haplotype analyses were carried out with microsatellite markers flanking 21 known arRP loci, including RP26. After the pathogenic gene was mapped to chromosome 2q31-q32, all 13 exons of CERKL were sequenced using both forward and reverse polymerase chain reaction primers as described.5 To discern 2 mutant alleles in the proband, polymerase chain reaction products of exon 1 and exon 5 of CERKL were cloned using the pGEM-T Easy Vector System (Promega Corp, Madison, Wisconsin) and multiple clones were sequenced.

The nonconsanguineous Chinese family with arRP includes 5 siblings. Both parents and their 2 daughters do not show any RP symptoms, but 3 sons are affected with RP (Figure 1). The proband (III:3) had night blindness at age 18 years and progressively lost visual acuity. Funduscopic examinations revealed attenuation of the retinal arteries and bony spicule pigmentation in the midperipheral retina but normal color of optic discs. A bull’s-eye–like appearance in the macular region was observed (Figure 1). Family members III:2 and III:4 had similar RP features, including onset of nyctalopia at about age 20 years. Currently, visual acuity in all 3 affected individuals is severely limited to the hand movement level, and no additional symptoms or ocular defects were observed.

Place holder to copy figure label and caption
Figure 1.

Pedigree structure and fundus photographs from the proband in the nonconsanguineous Chinese family with autosomal recessive retinitis pigmentosa. A, Haplotype results for markers on chromosome 2q31. Solid and open bars indicate disease and normal haplotypes, respectively. Solid squares indicate males with retinitis pigmentosa; open squares, healthy males; open circles, healthy females; and slash marks, deceased individuals. Haplotype analysis showed that all 3 male siblings of generation III inherited affected alleles separately from their carrier parents, whereas the 2 healthy sisters inherited both normal alleles. B, Fundus photographs from the proband (III:3). Arteriolar attenuation and bony spicule pigment deposit in the midperipheral retina are shown in both photographs.

Graphic Jump Location

Linkage and haplotype analysis mapped the disease-causing gene to RP26 (Figure 1). Direct DNA sequencing identified 2 compound heterozygous mutations, c.156_157insT in exon 1 and c.758delT in exon 5 of CERKL (Figure 2). The mother carried the c.156_157insT mutation and the father carried the c.758delT mutation. The 3 affected brothers carried both mutations, whereas the 2 unaffected sisters inherited both normal alleles from their parents. The c.156_157insT mutation introduces a stop codon at position 53 of CERKL, causing a prematurely truncated CERKL protein with only 52 amino acids. Mutation c.758delT causes a frameshift and substitutes 6 amino acids, 253-METDRI-258, by a short peptide of RKQTES, resulting in an abnormal protein with only 258 amino acid residues. Neither mutation was detected in 100 healthy Chinese Han control subjects.

Place holder to copy figure label and caption
Figure 2.

Identification of the compound heterozygous mutations in the nonconsanguineous Chinese family with autosomal recessive retinitis pigmentosa. A, Exon 1 sequence from a healthy individual. B, The sequence for mutation c.156_157insT introduces a stop codon at amino acid residue 53 of CERKL. C, Exon 1 sequence from an affected individual with heterozygous mutation c.156_157insT. D, Exon 5 sequence from a healthy individual. E, The sequence for mutation c.758delT causes a frameshift and substitutes 6 amino acids, 253-METDRI-258, by abnormal RKQTES and results in a truncated CERKL protein with only 258 amino acid residues. F, Exon 5 sequence from an affected individual with mutation c.758delT.

Graphic Jump Location

CERKL is a novel gene that has been recently associated with arRP. To date, only 3 mutations have been reported, including E257X, P106S, and a splicing mutation, all in consanguineous families.2,46 Interestingly, no significant clinical difference has been found among the patients with the 3 CERKL mutations. The patients with RP in this study have RP features and symptoms similar to those in the patients with the 3 reported CERKL mutations. In this study, we identified 2 compound heterozygous mutations in the CERKL gene, c.156_157insT and c.758delT, in a nonconsanguineous family with arRP. To our knowledge, this is the first report of compound heterozygous mutations of CERKL that cause arRP. Our results expand the spectrum of CERKL mutations causing arRP to the Chinese population.

ARTICLE INFORMATION

Correspondence: Dr Liu, Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, P. R. China (lium@mail.hust.edu.cn).

Author Contributions: Drs Q. K. Wang and Liu contributed equally to this work.

Financial Disclosure: None reported.

Funding/Support: This study was supported by grants 30771199, 30871386, and 30670857 from the Chinese National Natural Science Foundation.

Additional Contributions: We are grateful to the family for their participation in this study.

Hartong  DTBerson  ELDryja  TP Retinitis pigmentosa. Lancet 2006;368 (9549) 1795- 1809
PubMed Link to Article
Tuson  MMarfany  GGonzàlez-Duarte  R  et al.  Mutation of CERKL, a novel human ceramide kinase gene, causes autosomal recessive retinitis pigmentosa (RP26). Am J Hum Genet 2004;74 (1) 128- 138
PubMed Link to Article
Bornancin  FMechtcheriakova  DStora  S  et al.  Characterization of a ceramide kinase-like protein. Biochim Biophys Acta 2005;1687 (1-3) 31- 43
PubMed Link to Article
Ali  MRamprasad  VLSoumittra  N  et al.  A missense mutation in the nuclear localization signal sequence of CERKL (p.R106S) causes autosomal recessive retinal degeneration. Mol Vis 2008;141960- 1964
PubMed
Auslender  NSharon  DAbbasi  AHGarzozi  HJBanin  EBen-Yosef  T A common founder mutation of CERKL underlies autosomal recessive retinal degeneration with early macular involvement among Yemenite Jews. Invest Ophthalmol Vis Sci 2007;48 (12) 5431- 5438
PubMed Link to Article
Avila-Fernandez  ARiveiro-Alvarez  RVallespin  E  et al.  CERKL mutations and associated phenotypes in seven Spanish families with autosomal recessive retinitis pigmentosa. Invest Ophthalmol Vis Sci 2008;49 (6) 2709- 2713
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 2.

Identification of the compound heterozygous mutations in the nonconsanguineous Chinese family with autosomal recessive retinitis pigmentosa. A, Exon 1 sequence from a healthy individual. B, The sequence for mutation c.156_157insT introduces a stop codon at amino acid residue 53 of CERKL. C, Exon 1 sequence from an affected individual with heterozygous mutation c.156_157insT. D, Exon 5 sequence from a healthy individual. E, The sequence for mutation c.758delT causes a frameshift and substitutes 6 amino acids, 253-METDRI-258, by abnormal RKQTES and results in a truncated CERKL protein with only 258 amino acid residues. F, Exon 5 sequence from an affected individual with mutation c.758delT.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 1.

Pedigree structure and fundus photographs from the proband in the nonconsanguineous Chinese family with autosomal recessive retinitis pigmentosa. A, Haplotype results for markers on chromosome 2q31. Solid and open bars indicate disease and normal haplotypes, respectively. Solid squares indicate males with retinitis pigmentosa; open squares, healthy males; open circles, healthy females; and slash marks, deceased individuals. Haplotype analysis showed that all 3 male siblings of generation III inherited affected alleles separately from their carrier parents, whereas the 2 healthy sisters inherited both normal alleles. B, Fundus photographs from the proband (III:3). Arteriolar attenuation and bony spicule pigment deposit in the midperipheral retina are shown in both photographs.

Graphic Jump Location

Tables

References

Hartong  DTBerson  ELDryja  TP Retinitis pigmentosa. Lancet 2006;368 (9549) 1795- 1809
PubMed Link to Article
Tuson  MMarfany  GGonzàlez-Duarte  R  et al.  Mutation of CERKL, a novel human ceramide kinase gene, causes autosomal recessive retinitis pigmentosa (RP26). Am J Hum Genet 2004;74 (1) 128- 138
PubMed Link to Article
Bornancin  FMechtcheriakova  DStora  S  et al.  Characterization of a ceramide kinase-like protein. Biochim Biophys Acta 2005;1687 (1-3) 31- 43
PubMed Link to Article
Ali  MRamprasad  VLSoumittra  N  et al.  A missense mutation in the nuclear localization signal sequence of CERKL (p.R106S) causes autosomal recessive retinal degeneration. Mol Vis 2008;141960- 1964
PubMed
Auslender  NSharon  DAbbasi  AHGarzozi  HJBanin  EBen-Yosef  T A common founder mutation of CERKL underlies autosomal recessive retinal degeneration with early macular involvement among Yemenite Jews. Invest Ophthalmol Vis Sci 2007;48 (12) 5431- 5438
PubMed Link to Article
Avila-Fernandez  ARiveiro-Alvarez  RVallespin  E  et al.  CERKL mutations and associated phenotypes in seven Spanish families with autosomal recessive retinitis pigmentosa. Invest Ophthalmol Vis Sci 2008;49 (6) 2709- 2713
PubMed Link to Article

Correspondence

CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Please click the checkbox indicating that you have read the full article in order to submit your answers.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.

Multimedia

Some tools below are only available to our subscribers or users with an online account.

908 Views
13 Citations
×

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
Jobs