A Missense Mutation in RAB28 in a Family with Cone-Rod Dystrophy and Postaxial Polydactyly Prevents Localization of RAB28 to the Primary Cilium
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A Missense Mutation in RAB28 in a Family with Cone-Rod Dystrophy and Postaxial Polydactyly Prevents Localization of RAB28 to the Primary Cilium. / Jespersgaard, Cathrine; Hey, Amalie Brunbjerg; Ilginis, Tomas; Hjortshøj, Tina Duelund; Fang, Mingyan; Bertelsen, Mette; Bech, Niels; Jensen, Hanne; Larsen, Lasse Jonsgaard; Tümer, Zeynep; Rosenberg, Thomas; Brøndum-Nielsen, Karen; Møller, Lisbeth Birk; Grønskov, Karen.
I: Investigative Ophthalmology & Visual Science, Bind 61, Nr. 2, 2761939, 02.2020.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - A Missense Mutation in RAB28 in a Family with Cone-Rod Dystrophy and Postaxial Polydactyly Prevents Localization of RAB28 to the Primary Cilium
AU - Jespersgaard, Cathrine
AU - Hey, Amalie Brunbjerg
AU - Ilginis, Tomas
AU - Hjortshøj, Tina Duelund
AU - Fang, Mingyan
AU - Bertelsen, Mette
AU - Bech, Niels
AU - Jensen, Hanne
AU - Larsen, Lasse Jonsgaard
AU - Tümer, Zeynep
AU - Rosenberg, Thomas
AU - Brøndum-Nielsen, Karen
AU - Møller, Lisbeth Birk
AU - Grønskov, Karen
PY - 2020/2
Y1 - 2020/2
N2 - PURPOSE. Cone-rod dystrophy (CRD) is a rare hereditary eye disorder that causes progressive degeneration of cone and rod photoreceptors. More than 30 genes, including RAB28, have been associated with CRD; however, only a few RAB28 variants have been reported to be associated with CRD. In this study, we describe two brothers with CRD and a homozygous missense variant, c.55G>A (p.Gly19Arg), in RAB28. METHODS. The missense variant was identified as part of a study investigating underlying genetic defects in a large patient cohort (n = 667) using targeted next-generation sequencing of 125 genes associated with retinal dystrophy. Cellular localization of RAB28 and ciliogenesis in patient fibroblasts were investigated by immunofluorescence microscopy. The effect of the missense variant on RAB28 expression level was investigated by quantitative real-time PCR. RESULTS. Two brothers of a consanguineous couple presented with CRD, postaxial polydactyly (PAP), and myopia. Both brothers had a homozygous missense RAB28 variant located in the G1 box of the guanosine triphosphate/guanosine diphosphate binding domain of RAB28. This missense variant caused a considerable reduction of RAB28 localized to the cilia, whereas ciliogenesis seemed unaffected. CONCLUSIONS. The missense variant in RAB28 is classified as likely pathogenic with functional effect on protein localization. The combination of retinal dystrophy and PAP are well known from ciliopathies; however, more data are needed to finally conclude that the RAB28 variant described here is the cause of PAP in these brothers.
AB - PURPOSE. Cone-rod dystrophy (CRD) is a rare hereditary eye disorder that causes progressive degeneration of cone and rod photoreceptors. More than 30 genes, including RAB28, have been associated with CRD; however, only a few RAB28 variants have been reported to be associated with CRD. In this study, we describe two brothers with CRD and a homozygous missense variant, c.55G>A (p.Gly19Arg), in RAB28. METHODS. The missense variant was identified as part of a study investigating underlying genetic defects in a large patient cohort (n = 667) using targeted next-generation sequencing of 125 genes associated with retinal dystrophy. Cellular localization of RAB28 and ciliogenesis in patient fibroblasts were investigated by immunofluorescence microscopy. The effect of the missense variant on RAB28 expression level was investigated by quantitative real-time PCR. RESULTS. Two brothers of a consanguineous couple presented with CRD, postaxial polydactyly (PAP), and myopia. Both brothers had a homozygous missense RAB28 variant located in the G1 box of the guanosine triphosphate/guanosine diphosphate binding domain of RAB28. This missense variant caused a considerable reduction of RAB28 localized to the cilia, whereas ciliogenesis seemed unaffected. CONCLUSIONS. The missense variant in RAB28 is classified as likely pathogenic with functional effect on protein localization. The combination of retinal dystrophy and PAP are well known from ciliopathies; however, more data are needed to finally conclude that the RAB28 variant described here is the cause of PAP in these brothers.
KW - Cone-rod dystrophy
KW - Localization
KW - Molecular genetics
KW - Primary clilium
KW - RAB28
UR - http://www.scopus.com/inward/record.url?scp=85079783923&partnerID=8YFLogxK
U2 - 10.1167/iovs.61.2.29
DO - 10.1167/iovs.61.2.29
M3 - Journal article
C2 - 32084271
AN - SCOPUS:85079783923
VL - 61
JO - Investigative Ophthalmology & Visual Science
JF - Investigative Ophthalmology & Visual Science
SN - 0146-0404
IS - 2
M1 - 2761939
ER -
ID: 249478823