title: 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.
authors.affiliation: Department of Human Genetics, Radboud University Medical Centre, 6500 HB Nijmegen, the Netherlands.
authors.forename: Susanne
authors.initials: S
authors.lastname: Roosing
authors.forename: Klaus
authors.initials: K
authors.lastname: Rohrschneider
authors.forename: Avigail
authors.initials: A
authors.lastname: Beryozkin
authors.forename: Dror
authors.initials: D
authors.lastname: Sharon
authors.forename: Nicole
authors.initials: N
authors.lastname: Weisschuh
authors.forename: Jennifer
authors.initials: J
authors.lastname: Staller
authors.forename: Susanne
authors.initials: S
authors.lastname: Kohl
authors.forename: Lina
authors.initials: L
authors.lastname: Zelinger
authors.forename: Theo A
authors.initials: TA
authors.lastname: Peters
authors.forename: Kornelia
authors.initials: K
authors.lastname: Neveling
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.forename: L Ingeborgh
authors.initials: LI
authors.lastname: van den Born
authors.forename: Carel B
authors.initials: CB
authors.lastname: Hoyng
authors.forename: Caroline C W
authors.initials: CC
authors.lastname: Klaver
authors.forename: Ronald
authors.initials: R
authors.lastname: Roepman
authors.forename: Bernd
authors.initials: B
authors.lastname: Wissinger
authors.forename: Eyal
authors.initials: E
authors.lastname: Banin
authors.forename: Frans P M
authors.initials: FP
authors.lastname: Cremers
authors.forename: Anneke I
authors.initials: AI
authors.lastname: den Hollander
mesh_terms: D000293:Adolescent; D000328:Adult; D017398:Alternative Splicing; D000818:Animals; D002648:Child; D002874:Chromosome Mapping; D002923:Cilia / Q000378:metabolism / Q000473:pathology; D018389:Codon, Nonsense / Q000235:genetics; D005786:Gene Expression Regulation; D005808:Genes, Recessive; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006720:Homozygote; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D010375:Pedigree; D055212:Photoreceptor Connecting Cilium / Q000378:metabolism / Q000473:pathology; D017368:Protein Prenylation; D021381:Protein Transport; D051381:Rats; D012160:Retina / Q000201:enzymology / Q000473:pathology; D055213:Retinal Pigment Epithelium / Q000201:enzymology / Q000473:pathology; D017948:Retinal Rod Photoreceptor Cells / Q000201:enzymology / Q000473:pathology; D012174:Retinitis Pigmentosa / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D014792:Visual Acuity; D020691:rab GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D018389:Codon, Nonsense; D007527:Isoenzymes; C503250:RAB28 protein, human; D020691:rab GTP-Binding Proteins