Identification of recurrent and novel mutations in TULP1 in Pakistani families with early-onset retinitis pigmentosa

Purpose: To identify the genetic defects underlying retinitis pigmentosa (RP) in Pakistani families. Methods: Genome-wide high-density single-nucleotide-polymorphism microarray analysis was performed using the DNA of nine affected individuals from two large families with multiple consanguineous marriages. Data were analyzed to identify homozygous regions that are shared by affected sibs in each family. Sanger sequencing was performed for genes previously implicated in autosomal recessive RP and allied retinal dystrophies that resided in the identified homozygous regions. Probands from both families underwent fundus examination and electroretinogram measurements. Results: The tubby-like protein 1 gene (TULP1) was present in the largest homozygous region in both families. Sequence analysis identified a previously reported mutation (c.1138A>G; p.Thr380Ala) in one family and a novel pathogenic variant (c.1445G>A; p.Arg482Gln) in the other family. Both variants were found to be present in a homozygous state in all affected individuals, were heterozygous present in the unaffected parents, and heterozygous present or absent in normal individuals. Affected individuals of both families showed an early-onset form of RP. Conclusions: Homozygosity mapping, combined with candidate-gene analysis, successfully identified genetic defects in TULP1 in two large Pakistani families with early-onset retinitis pigmentosa. The major cause of inherited blindness in humans is retinitis pigmentosa (RP; OMIM 268000). The clinical symptoms of RP are the loss of night vision in the early phase of disease, later followed by peripheral vision loss, tunnel vision, and sometimes complete blindness [1]. Progression of the disease is mainly caused by the gradual loss of rod photoreceptor cells, which are mostly responsible for vision under low light conditions, and the subsequent loss of cone photoreceptor cells, which are involved in color vision under bright light conditions. The clinical diagnosis is based on fundus examination and electrophysiological analysis of rod and cone photoreceptor-cell function by measuring the scotopic and photopic responses, respectively, using electroretinography (ERG). The disease’s characteristics are the presence of pigmentary deposits (bone spicules) in the peripheral fundus, diminished or no ERG responses from rod