title: Mutation spectrum in RAB3GAP1, RAB3GAP2, and RAB18 and genotype-phenotype correlations in warburg micro syndrome and Martsolf syndrome.
abstract: Warburg Micro syndrome and Martsolf syndrome (MS) are heterogeneous autosomal-recessive developmental disorders characterized by brain, eye, and endocrine abnormalities. Causative biallelic germline mutations have been identified in RAB3GAP1, RAB3GAP2, or RAB18, each of which encode proteins involved in membrane trafficking. This report provides an up to date overview of all known disease variants identified in 29 previously published families and 52 new families. One-hundred and forty-four Micro and nine Martsolf families were investigated, identifying mutations in RAB3GAP1 in 41% of cases, mutations in RAB3GAP2 in 7% of cases, and mutations in RAB18 in 5% of cases. These are listed in Leiden Open source Variation Databases, which was created by us for all three genes. Genotype-phenotype correlations for these genes have now established that the clinical phenotypes in Micro syndrome and MS represent a phenotypic continuum related to the nature and severity of the mutations present in the disease genes, with more deleterious mutations causing Micro syndrome and milder mutations causing MS. RAB18 has not yet been linked to the RAB3 pathways, but mutations in all three genes cause an indistinguishable phenotype, making it likely that there is some overlap. There is considerable genetic heterogeneity for these disorders and further gene identification will help delineate these pathways.
authors: MRC Human Genetics Unit, Medical Research Council and Institute of Genetics and Molecular Medicine, University of Edinburgh, Scotland, UK.
authors: Mark T
authors: MT
authors: Handley
authors: Deborah J
authors: DJ
authors: Morris-Rosendahl
authors: Stephen
authors: S
authors: Brown
authors: Fiona
authors: F
authors: Macdonald
authors: Carol
authors: C
authors: Hardy
authors: Danai
authors: D
authors: Bem
authors: Sarah M
authors: SM
authors: Carpanini
authors: Guntram
authors: G
authors: Borck
authors: Loreto
authors: L
authors: Martorell
authors: Claudia
authors: C
authors: Izzi
authors: Francesca
authors: F
authors: Faravelli
authors: Patrizia
authors: P
authors: Accorsi
authors: Lorenzo
authors: L
authors: Pinelli
authors: Lina
authors: L
authors: Basel-Vanagaite
authors: Gabriela
authors: G
authors: Peretz
authors: Ghada M H
authors: GM
authors: Abdel-Salam
authors: Maha S
authors: MS
authors: Zaki
authors: Anna
authors: A
authors: Jansen
authors: David
authors: D
authors: Mowat
authors: Ian
authors: I
authors: Glass
authors: Helen
authors: H
authors: Stewart
authors: Grazia
authors: G
authors: Mancini
authors: Damien
authors: D
authors: Lederer
authors: Tony
authors: T
authors: Roscioli
authors: Fabienne
authors: F
authors: Giuliano
authors: Astrid S
authors: AS
authors: Plomp
authors: Arndt
authors: A
authors: Rolfs
authors: John M
authors: JM
authors: Graham
authors: Eva
authors: E
authors: Seemanova
authors: Pilar
authors: P
authors: Poo
authors: Angels
authors: A
authors: García-Cazorla
authors: Patrick
authors: P
authors: Edery
authors: Ian J
authors: IJ
authors: Jackson
authors: Eamonn R
authors: ER
authors: Maher
authors: Irene A
authors: IA
authors: Aligianis
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002386:Cataract / Q000235:genetics* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D005838:Genotype; D006801:Humans; D007006:Hypogonadism / Q000235:genetics* / Q000473:pathology; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics* / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010641:Phenotype; D017386:Sequence Homology, Amino Acid; D020691:rab GTP-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D020692:rab3 GTP-Binding Proteins / Q000737:chemistry / Q000235:genetics*
chemical_list: C484168:RAB18 protein, human; C555465:RAB3GAP2 protein, human; C580955:RAB3GAP1 protein, human; D020691:rab GTP-Binding Proteins; D020692:rab3 GTP-Binding Proteins