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.
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.
Tang Z, Wang Z, Wang Z, Ke T, Wang QK, Liu M. Novel Compound Heterozygous Mutations in CERKL Cause Autosomal Recessive Retinitis Pigmentosa in a Nonconsanguineous Chinese Family. Arch Ophthalmol. 2009;127(8):1077-1078. doi:10.1001/archophthalmol.2009.207
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.
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.
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.2,4- 6 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.
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 (email@example.com).
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.