The Mutatinal Analysis Of Pathogenic Genes In Two Chinese Autosomal Recessive Families With Retinitis Pigmentosa And Cataract

Retinitis pigmentosa(RP) is an inherited retinal degenerative disease with a global prevalence ranging from 1/3000 to 1/5000. The typical clinical manifestations of RP include night blindness, progressive constricted visual field and loss of vison, and usually accompanied with strabismus, nystagmus, cataract and refractive error. The coincidence of cataract is more than 40%. In this study, we collected two Chinese autosomal recessive families with RP(arRP) and cataract from Henan province and studied the molecular pathogenesis of patients in the families by linkage analysis, candidate gene and exome sequencing technologies, the results are as follows:Four-generation Chinese family1 including three patients which came from two exchanging marriage families, with arRP and radiated cataract has be identified. The fundus of these patients showed retinal spicule pigment depositions, attenuated retinal blood vessels, pale optic disk, macula atrophy and posterior subcapsular cataract in both eyes. Family1 was studied by microsatellite markers for linkage analyzing and found that the pathogenic gene located between markers D14S63 and D14S1050 in the chromosome14, which containing two known causative genes SPATA7 and RDH12. We found that proband carried a compound heterozygous mutation c.184C>T/p.R62 X, c.437T>A/p.V146 D in RDH12 and a heterozygous variation c.995T>C/p.I332 T in SPATA7. RFLP analysis certified that the compound heterozygous mutation of RDH12 co-segregated with the disease in the family, and these two mutations were not detected in 100 normal Chinese people. Arginine at codon 62 and valine at codon 146 are highly conservation from Danio rerio to Homo sapiens. The mutations c.184C>T and c.437T>A have been previously reported in RP patients, thus considered both mutations contributing to the disease. These results showed that the compound heterozygous mutation in RDH12 might be the genetic cause of this disease in family1. The heterozygous variation c.995T>C/p.I332 T in SPATA7 was detected in three patients, whether it has a relationship with the patients’ clinical phenotype is still unclear. It was up to 11.8% of RP cases with RDH12 mutations could be accounted for all RP patients worldwide, and the coincidence of cataract was higher than 40%. Including this study, there were only six RP families andeight sporadic RP patients with RDH12 mutations reported in China, which accounted for4.6% of Chinese cases, and the incidence of cataract was 30%. Statistics found 12 out of20 Chinese RP patients with RDH12 mutations carrying c.437T>A, suggesting that c.437T>A was a mutation hot site in Chinese RP patients..The fundus examinations being carried out in three patients which from consanguineous family2, showed retinal spicule and crumby pigment deposits,chorioretinal severe atrophy and dustlike posterior subcapsular cataract in both eyes.Notably, tiny yellow crystalline deposits were seen in one patient’s fundus, but no appeared in retina of proband and her second sister. By applying whole exome and Sanger sequencing technology, we identified a homozygous variation c.1198C>T in CYP4V2 gene which was predicted to result in the highly conserved arginine to cysteine at amino acid residue 400 in CYP4V2. The mutation has been identified in RP patients, implying that it might exert genetic contribution to the disease. Thus we considered the homozygous mutation was the cause of disease in family2. Our study proved again that the clinical phenotype caused by CYP4V2 mutations was heterogeneous, and provided important data for comprehending the types and frequency of CYP4V2 mutations in patients with RP.