Homozygosity Mapping Reveals Null Mutations in FAM161A as a Cause of Autosomal-Recessive Retinitis Pigmentosa

Abstract

Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal degenerations caused by mutations in at least 45 genes. Using homozygosity mapping, we identified a ∼4 Mb homozygous region on chromosome 2p15 in patients with autosomal-recessive RP (arRP). This region partially overlaps with RP28, a previously identified arRP locus. Sequence analysis of 12 candidate genes revealed three null mutations in FAM161A in 20 families. RT-PCR analysis in 21 human tissues revealed high levels of FAM161A expression in the retina and lower levels in the brain and testis. In the human retina, we identified two alternatively spliced transcripts with an intact open reading frame, the major one lacking a highly conserved exon. During mouse embryonic development, low levels of Fam161a transcripts were detected throughout the optic cup. After birth, Fam161a expression was elevated and confined to the photoreceptor layer. FAM161A encodes a protein of unknown function that is moderately conserved in mammals. Clinical manifestations of patients with FAM161A mutations varied but were largely within the spectrum associated with arRP. On funduscopy, pallor of the optic discs and attenuation of blood vessels were common, but bone-spicule-like pigmentation was often mild or lacking. Most patients had nonrecordable electroretinographic responses and constriction of visual fields upon diagnosis. Our data suggest a pivotal role for FAM161A in photoreceptors and reveal that FAM161A loss-of-function mutations are a major cause of arRP, accounting for ∼12% of arRP families in our cohort of patients from Israel and the Palestinian territories.

Genetics and Disease Expression in the CNGA3 Form of Achromatopsia

“…9 The current study is the first comprehensive clinical and genetic analysis of ACHM in the Israeli and Palestinian populations. Similar to previous reports of other inherited retinal phenotypes (such as retinitis pigmentosa 33,34 ), our cohort displays a different distribution of genes and mutations compared with other studied populations (mainly from Europe and North America). The most common cause of ACHM in Western populations (CNGB3 c.1148delC) was found to cause the disease in only 8% of families (4/49) studied here, with all 4 families sharing the same origin (North African Jewish).…”

Trio-based exome sequencing arrests de novo mutations in early-onset high myopia

“…Mutations in GRM6 are reported in HM (32) and nyctalopia (33). In addition to these two known genes, we identified a unique candidate gene, FAM161A, which is involved in microtubule stabilization (34,35). Proband H45 harbors a nonsense mutation (p.Q302X) in FAM161A.…”

Diverse clinical phenotypes associated with a nonsense mutation in FAM161A

“…The major isoform of the protein is formed of 660 amino acids (NCBI RefSeq ID NM_032180.2), whereas the less common isoform (formed by retention of exon 4; NCBI RefSeq ID NM_001201543.1) comprises 716 amino acids. 2 Both isoforms contain a 277-amino-acid domain (UPF0564) that mediates microtubule association 5 and has been previously identified in at least 15 other human proteins. The UPF0564 domain contains three conserved coiled-coil motifs that, in other proteins, mediate oligomerisation and proteinprotein interactions.…”

“…[1][2][3] The gene is expressed in several tissues including the heart, brain, liver, lung, kidney, and muscle, but expression is particularly elevated in the retina. In the murine retina, FAM161A localises to photoreceptor cells during development, and to the inner segment of photoreceptor cells and outer plexiform layer in the adult retina.…”