Yan Ma, Xun Wang, Nadav Shoshany, Xiaodong Jiao, Adrian Lee, Gregory Ku, Emma L. Baple, James Fasham, Raheela Nadeem, Muhammad Asif Naeem, Sheikh Riazuddin, S. Amer Riazuddin, Andrew H. Crosby, J. Fielding Hejtmancik | Frontiers in Genetics | 21 March 2022 | Vol 13 | doi.org/10.3389/fgene.2022.804924
Background A CLCC1 c. 75C > A (p.D25E) mutation has been associated with autosomal recessive pigmentosa in patients in and from Pakistan. CLCC1 is ubiquitously expressed, and knockout models of this gene in zebrafish and mice are lethal in the embryonic period, suggesting that possible retinitis pigmentosa mutations in this gene might be limited to those leaving partial activity. In agreement with this hypothesis, the mutation is the only CLCC1 mutation associated with retinitis pigmentosa to date, and all identified patients with this mutation share a common SNP haplotype surrounding the mutation, suggesting a common founder.
Methods SNPs were genotyped by a combination of WGS and Sanger sequencing. The original founder haplotype, and recombination pathways were delineated by examination to minimize recombination events. Mutation age was estimated by four methods including an explicit solution, an iterative approach, a Bayesian approach and an approach based solely on ancestral segment lengths using high density SNP data.
Results All members of each of the nine families studied shared a single autozygous SNP haplotype for the CLCC1 region ranging from approximately 1–3.5 Mb in size. The haplotypes shared by the families could be derived from a single putative ancestral haplotype with at most two recombination events. Based on the haplotype and Gamma analysis, the estimated age of the founding mutation varied from 79 to 196 generations, or approximately 2,000–5,000 years, depending on the markers used in the estimate. The DMLE (Bayesian) estimates ranged from 2,160 generations assuming a population growth rate of 0–309 generations assuming a population growth rate of 2% with broad 95% confidence intervals.
Conclusion These results provide insight into the origin of the CLCC1 mutation in the Pakistan population. This mutation is estimated to have occurred 2000–5,000 years ago and has been transmitted to affected families of Pakistani origin in geographically dispersed locations around the world. This is the only mutation in CLCC1 identified to date, suggesting that the CLCC1 gene is under a high degree of constraint, probably imposed by functional requirements for this gene during embryonic development.
Introduction
Retinitis pigmentosa (RP [MIM 268000]) is a clinically and genetically heterogeneous disorder affecting approximately one in 4,000 individuals worldwide (Hartong et al., 2006). Clinically, patients initially exhibit night blindness followed by progressive loss of peripheral visual fields, eventually culminating in compromise or even complete loss of central vision. Typical fundus changes include bone spicule-like pigmentation in the mid-peripheral retina, waxy pallor of the optic discs, and attenuation of retinal blood vessels. Since RP initially affects the rod photoreceptors, followed by the degeneration of cone photoreceptors, patients often have severely diminished or extinguished rod response in electroretinography (ERG) even in early stages of the disease, while the cone response is relatively preserved initially but decreases and becomes undetectable as the disease progresses (Bird, 1995). Genetic inheritance patterns of RP include autosomal-dominant (about 30–40% of cases), autosomal-recessive (50–60%), and X-linked (5–15%) inheritance (Bunker et al., 1984; Rivolta et al., 2002). More than 82 causative genes have been identified for RP so far, of which 58 genes have been identified in families with autosomal recessive RP (arRP) (Daiger et al., 2021).
At least in part reflecting social and economic considerations, the frequency of consanguineous marriages in Pakistan is among the highest in the world (Bittles, 2001), ranging from 15 to 35% (Hamamy et al., 2011). In reviewing 146 genetically resolved arRP Pakistani families, Khan et al. found only 4 (2.7%) with compound heterozygous mutations (Khan et al., 2014), emphasizing the role of consanguinity on the incidence of arRP in this population. Not only does the high frequency of consanguinity in the Pakistani population bring out autosomal recessive alleles, but it also increases the likelihood that sharing of variations by different families is likely to be the result of the variant allele being derived from a common ancestor, especially if the families that share the same variation also share a common intragenic SNP haplotype for the associated gene.
Chloride channel CLIC like 1 (CLCC1) is a transmembrane channel protein with high permeability for anions, in particular chloride, localized to the endoplasmic reticulum (ER) and in some cell types possibly the Golgi apparatus and Nucleus (Nagasawa et al., 2001). The CLCC1 gene spans 33 kb, comprising 13 exons encoding a 551 amino acid protein. Li et al. (Li et al., 2018) demonstrated that Clcc1 is highly expressed in the mouse retina, and modestly expressed in the iris, optic nerve, sclera, and cornea. Immunohistochemistry in the normal adult human eye demonstrated CLCC1 expression extensively in the retina and optic nerve, suggesting a physiologic role of CLCC1 in retinal function. Within the retina, CLCC1 staining was more intense in the lamina cribrosa, optic nerve, ganglion cell layer, inner and outer nuclear layers, and retinal pigment epithelium (RPE). The CLCC1 NM_145,543.2:c.75C > A (p.D25E) missense mutation in CLCC1 was found in seven Pakistani families and one British-Bangladeshi family with arRP mapping to chromosome 1p13 (RP32; 609,913). Recent additional screening has found one new family (61334) carrying the same mutation, bringing the total number of families to nine and accounting for about 6% of genetic cases of arRP in Pakistani families (Li et al., 2017).
The present study was undertaken to investigate the possible common ancestry of the nine Pakistani and Pakistani-derived families carrying the c.75C > A mutation, to define the likely recombination and mutational events that would be required to occur if they did have a common founder, to estimate the approximate age of the putative founder mutation and to correlate the history and geographic distribution of this mutation with the population history of Pakistan. To achieve these goals, we performed haplotype analysis of 99 intragenic SNPs flanking the c.75C > A CLCC1 mutation, derived the recombinational pathways requiring the fewest recombination events to yield the currently observed haplotypes, and estimated the number of generations that have occurred since the original mutation in the founder.
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