FAM161A, a Novel Centrosomal-Ciliary Protein Implicated in Autosomal Recessive Retinitis Pigmentosa

Abstract

Retinitis pigmentosa (RP) is an inherited disease of the retina leading to vision impairment due to progressive photoreceptor cell death. Homozygous and compound heterozygous null mutations in the CRX-regulated FAM161A gene of unknown function were identified as a cause for autosomal recessive RP (RP28) in patients from India, Germany, Israel, the Palestinian territories, and the USA. The FAM161A protein has been found to be localized to the connecting cilium, the basal body, and the adjacent centriole in mammalian photoreceptors and was also present in synaptic layers and ganglion cells of the retina. In addition, FAM161A was shown to be part of microtubule-organizing centers in cultured cells and associates with the intracellular microtubule network. Moreover, FAM161A directly binds to microtubules and increases the acetylation of α-tubulin. An evolutionary highly conserved, C-terminal protein domain (UPF0564) of FAM161A was shown to mediate microtubule association, homo- and heterotypic interaction among UPF0564-containing proteins and binding to several ciliopathy-associated proteins. In summary, FAM161A is a novel centrosomal-ciliary protein that likely is implicated in the regulation of microtubule-based cellular processes in the retina.

Unique combination of clinical features in a large cohort of 100 patients with retinitis pigmentosa caused by FAM161A mutations

“…The most frequent initial symptom was night blindness, followed by loss of visual fields and decrease in visual acuity. Most of the patients reported that the initial symptom of night blindness appeared in childhood (39 patients before the age of 10) or during adolescence (26 patients between the ages of [11][12][13][14][15][16][17][18][19][20], which represents 78% of the 83 patients for whom this data was available ( Supplementary Table S2).…”

“…in photoreceptor cells [11][12][13] , and is part of the cytoskeleton fraction of the cilia and a component of the human centrosome 14,15 . It was also found to be a member of the Golgi-centrosomal interactome, a network of proteins interconnecting Golgi maintenance, intracellular transport and centrosome organization 16 .…”

MLT1 links cytoskeletal asymmetry to organelle placement in chlamydomonas

“…2A). These basic regions may interact with the conserved, acidic C-terminal tail of tubulin, known to bind basic sequences in a variety of proteins [Bai et al, 2013;Bhogaraju et al, 2013;Gigant et al, 2014;Zach and Stohr, 2014;Wang et al, 2014b]. Based on this idea, a MLT1 gene was constructed in which all sixteen codons specifying Lys or Arg in the largest basic island (asterisk in Fig.…”

It takes two (centrioles) to tango

“…However, centrioles also have several important, specialized roles in differentiating cells. They help direct asymmetrical divisions to drive cell differentiation (Lerit et al 2013, Chen et al 2016, are essential for sensory functions such as sight (Roosing et al 2014, Zach & Stohr 2014 and they are critical for lung function (Yan et al 2016). These centriolar roles are well studied, but one area in need of further research is the function of centrioles during fertilization and reproduction.…”