Mutations in RAB28, Encoding a Farnesylated Small GTPase, Are Associated with Autosomal-Recessive Cone-Rod Dystrophy

Abstract

The majority of the genetic causes of autosomal-recessive (ar) cone-rod dystrophy (CRD) are currently unknown. A combined approach of homozygosity mapping and exome sequencing revealed a homozygous nonsense mutation (c.565C>T [p.Glu189*]) in RAB28 in a German family with three siblings with arCRD. Another homozygous nonsense mutation (c.409C>T [p.Arg137*]) was identified in a family of Moroccan Jewish descent with two siblings affected by arCRD. All five affected individuals presented with hyperpigmentation in the macula, progressive loss of the visual acuity, atrophy of the retinal pigment epithelium, and severely reduced cone and rod responses on the electroretinogram. RAB28 encodes a member of the Rab subfamily of the RAS-related small GTPases. Alternative RNA splicing yields three predicted protein isoforms with alternative C-termini, which are all truncated by the nonsense mutations identified in the arCRD families in this report. Opposed to other Rab GTPases that are generally geranylgeranylated, RAB28 is predicted to be farnesylated. Staining of rat retina showed localization of RAB28 to the basal body and the ciliary rootlet of the photoreceptors. Analogous to the function of other RAB family members, RAB28 might be involved in ciliary transport in photoreceptor cells. This study reveals a crucial role for RAB28 in photoreceptor function and suggests that mutations in other Rab proteins may also be associated with retinal dystrophies.

Homozygous missense variant in the human CNGA3 channel causes cone-rod dystrophy

“…1-3 CRD can manifest under a variety of inheritance models, though the autosomal recessive mode of inheritance is the most prevalent. To date, eight genes responsible for autosomal recessive CRD have been identified: ABCA4 (OMIM#601691), 4 ADAM9 (OMIM#602713), 5 C8orf37 (OMIM#614477), 6 CERKL (OMIM#608381), 7 EYS (OMIM#612424), 8 RPGRIP1 (OMIM#605446), 9 RAB28 (OMIM#612994) 10 and TULP1 (OMIM#602280). 11 However, the known variants do not account for all cases of CRD.…”

The role of primary cilia in the development and disease of the retina

“…41 Once the basal body has docked at the apical cell surface, binding of post-Golgi vesicles to the primary vesicle expands the membrane to form the ciliary vesicle, allowing the ciliary bud to extend to form the axoneme. This ciliary vesicle then fuses with the plasma membrane and the CC extends toward the RPE.…”

Genomic Approaches For the Discovery of Genes Mutated in Inherited Retinal Degeneration

“…For example, two novel genes underlying autosomal dominant exudative vitreoretinopathy, TSPAN12 and ZNF408, were identified by combining linkage mapping and targeted (to a 40 Mb genomic region) or exome NGS, respectively (Nikopoulos et al 2010;Collin et al 2013). Homozygosity mapping combined with exome sequencing identified several other novel IRD genes (for example MAK, DHDDS, and RAB28) (Ozgul et al 2011;Tucker et al 2011;Zelinger et al 2011;Zuchner et al 2011;Roosing et al 2013). …”

“…At the moment, the highest probe density of 2.7 M is provided by CytoScan HD (Affymetrix); among those, 700,000 SNPs have a high minor allele frequency, which is very informative for linkage and homozygosity mapping, or for the detection of uniparental isodisomy (Roosing et al 2013). Two million probes on the array are quantitatively assessed to detect deletions, duplications, and amplifications larger than 20 kb.…”