Abstract
Purpose :
To study the causative mutations and phenotypic spectrum in the Israeli Jewish albino population.
Methods :
Phenotypic evaluation included description of hair, eye and skin color, presence of nevi and ability to tan. Eye examination included visual acuity, presence of nystagmus, transillumination, visibility of choroidal vessels and hypoplasia of the macula. Genetic investigation included origin of grandparents and detailed pedigree analysis. Mutation analysis was performed on extracted blood DNA by PCR followed by restriction enzyme digestion, haplotype analysis and sequencing.
Results :
We have screened almost 500 Israeli Jewish albinos for mutations in TYR, P, SLC45A2, GPR143 and HPS3 genes, causing OCA1, OCA2, OCA4, OA1 and HPS3, respectively. At least one mutation was detected in about 90% of the tested albinos. TYR is the major gene causing albinism (70%), and P mutations were detected in about 28% of patients. While the two causative mutations were identified in 98% of albinos with TYR mutations, in only 61% of albinos with P mutation the two mutations were identified, though linkage to P was demonstrated in several large families. While sequencing the P gene in albinos with one P mutation, many polymorphisms were detected. Comparison of haplotypes of the allele with unidentified mutation indicated more than one missing P mutation. Detailed phenotypes were correlated with TYR, P and SLC45A2 mutations. While the severe phenotype, OCA1A, was always caused by mutations in TYR, no correlation exists between OCA1B and OCA2 phenotypes and the causative genes / mutations; the identified mutations can be divided into "severe" (causing OCA1A) "mild" and "very mild" (OCA1B/2) – with overlapping spectrum of phenotypes. Combination of "severe" and "mild" mutations resulted in severe OCA1B/2 phenotype. Interestingly, the phenotype of albinos having two mutations in either TYR or P and one mutation in the other gene was within the phenotypic spectrum of the major gene, and was not influenced by the additional mutation.
Conclusions :
TYR and P are the causative genes among Jewish albinos. High detection rate was demonstrated for TYR mutations, while several P mutations were not identified by exon sequencing. In groups of albinos sharing the same genotype the spectrum of clinical manifestations can be determined and used for prediction of the range of severity of clinical manifestations in albino newborns.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.