Mutation Survey of Known LCA Genes and Loci in the Saudi Arabian Population

Departments of Molecular and Human Genetics.
Investigative ophthalmology & visual science (Impact Factor: 3.4). 11/2008; 50(3):1336-43. DOI: 10.1167/iovs.08-2589
Source: PubMed


The purpose of this study was to perform a comprehensive survey of all known Leber congenital amaurosis (LCA) genes and loci in a collection of 37 consanguineous LCA families from Saudi Arabia.
Direct PCR and sequencing were used to screen 13 known LCA genes (GUCY2D, CRX, RPE65, TULP1, AIPL1, CRB1, RPGRIP1, LRAT, RDH12, IMPDH1, CEP290, RD3, LCA5). In addition, families without mutations identified were further screened with STR markers around these 13 known LCA genes and two loci.
Disease-causing mutations were identified in nine of the 37 families: five in TULP1, two in CRB1, one in RPE65, and one in GUCY2D. Mutations in known genes only accounted for 24% of the Saudi families--much less than what has been observed in the European population (65%). Phenotype-genotype analysis was carried out to investigate the LCA disease penetrance for all families whose mutations identified. All identified mutations were found to segregate perfectly with the disease phenotype. On the other hand, severity of the disease varies for different patients carrying the same mutation and even within the same family. Furthermore, based on homozygosity mapping with both STR and SNP markers, one family is likely to map to the LCA3 locus.
These results underscore the importance of studying LCA disease families from different ethnic backgrounds to identify additional novel LCA disease genes. Furthermore, perfect segregation between mutation and disease indicates that LCA is fully penetrant. However, phenotypic variations among patients carrying the same mutation suggest that at least some of the variations in the clinical phenotype is due to modification from the genetic background, environment, or other factors.

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Available from: Rui Chen, Oct 20, 2014
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    • "Including our findings, 26 different TULP1 mutations have been identified in 33 families (Table 2). TULP1 mutations were found in 4.3% (10/231) of LCA families [14,18,24,25,27,29,30] and 2.4% (23/948) of arRP families [15,19-24,26,28,30,31,50]. TULP1 mutations causing arRP or LCA include two nonsense, two frame-shift, and seven splice-site mutations; a six-base-pair duplication; and 14 missense mutations (Table 2). Splice-site and protein-truncating mutations are distributed throughout the gene (Figure 6A), whereas the missense mutations are only present in the C-terminal tubby domain of TULP1 (Figure 6B). "
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    • "The presence of macular involvement was also a feature of patients with a mutation in TULP1 reported in our earlier study [12]. Contrary to reports in the literature in which nystagmus was a feature of patients with TULP1 mutations [3,15,16], no nystagmus was present in our patients. Other clinical features were characteristic of RP. "
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    • "In northern Pakistan, the genes most commonly mutated in LCA are RPGRIP1 (29% of families), AIPL1 (21% of families), and LCA5 (21% of families); whereas in Caucasian populations, mutations in RPGRIP1, AIPL1, and LCA5 account for only 4.2%, 5.3%, and 1.8% of LCA cases, respectively [2]. Although CEP290 is the most commonly identified mutant gene in Caucasian LCA patients, accounting for 15% of LCA cases [29], mutations in CEP290 have not been detected in LCA patients from Korea [30], Saudi Arabia [31], northern Pakistan [32], or southern India [33]. An understanding of the frequency spectrum of variants in these 15 genes in different populations will not only facilitate genetic diagnosis and genetic counseling for this disastrous disorder, but will also identify patients who may potentially benefit from gene therapy or other possible interventions [31]. "
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