Homozygosity mapping reveals new nonsense mutation in the FAM161A gene causing autosomal recessive retinitis pigmentosa in a Palestinian family

Abstract

Purpose: Retinitis pigmentosa (RP) is a heterogenous group of inherited retinal degenerations caused by mutations in at least 45 genes. Recently, the FAM161A gene was identified as the causative gene for RP28, an autosomal recessive form of RP.

Methods: We performed a clinical and molecular genetic study of a consanguineous Palestinian family with two three siblings affected with retinitis pigmentosa. DNA samples were collected from the index patient, his father, his affected sister, and two non-affected brothers. DNA sample from the index was subjected to high resolution genome-wide SNP array. Assuming identity-by-descent in this consanguineous family we applied homozygosity mapping to identify disease causing genes.

Results: The index patient reported night blindness since the age of 20 years, followed by moderate disease progression with decrease of peripheral vision, the development of photophobia and later on reduced central vision. At the age of 40 his visual acuity was counting fingers (CF) for both eyes, color discrimination was not possible and his visual fields were severely constricted. Funduscopic examination revealed a typical appearance of advanced RP with optic disc pallor, narrowed retinal vessels, bone-spicule like pigmentary changes in the mid-periphery and atrophic changes in the macula. His younger affected brother (37 years) was reported with overall milder symptoms, while the youngest sister (21 years) reported problems only with night vision. Applying high-density SNP arrays we identified several homozygous genomic regions one of which included the recently identified FAM161A gene mutated in RP28-linked autosomal recessive RP. Sequencing analysis revealed the presence of a novel homozygous nonsense mutation, c.1003C>T/p.R335X in the index patient and the affected sister.

Conclusion: We identified an RP28-linked RP family in the Palestinian population caused by a novel nonsense mutation in FAM161A. RP in this family shows a typical disease onset with moderate to rapid progression into severe visual impairment including central vision in the index and overall milder symptoms in the younger brother and sister.

Figure 1

Morphological findings. Fundus pictures of the right (R) and left eye (L) of the index patient showing pallor optic discs, attenuated vessels, and characteristic pigment changes in the mid-periphery.

Figure 2

Pedigree and genetic findings. The index patient and his youngest sister show a homozygous nonsense mutation, c.1003C>T/p.R335X, while both the father and one of the unaffected brothers are heterozygous for the mutation and the other unaffected brother does not carry the mutation. The sequencing electropherograms show the homozygous mutant sequence (top) in comparison with a wildtype control sequence (bottom).

Figure 3

Structure of the FAM161A gene and localization of a currently known RP-associated mutation. Black bars indicate coding exons or exon segments whereas white bars represent the 5′ and 3′ untranslated region (UTR), respectively. The transcript splicing pattern is depicted below showing the two alternatively spliced isoforms including or lacking exon 3a. Most currently known mutations localize to exon 3; the novel p.R335X mutation found in this study is shown in red.

Figure 4

GC profile of exon 3 of FAM161A. The GC profile shows local segments of significantly elevated GC content.