title: Novel mutations in the TRIM37 gene in Mulibrey Nanism.
abstract: Mulibrey nanism is an autosomal recessive prenatal-onset growth disorder of unknown pathogenesis. The main clinical features are pre- and postnatal growth failure, characteristic dysmorphic craniofacial features, heart disease, and hepatomegaly. Five truncating mutations in the TRIM37 gene have previously been reported in Mulibrey nanism patients. The TRIM37 protein encodes a novel protein of unknown function. It contains a tripartite motif (TRIM, also denoted the RING-B-box-Coiled-coil or RBCC domain) and a TRAF (tumor necrosis factor-receptor associated factor) domain. TRIM37 localizes to peroxisomes classifying Mulibrey nanism as a peroxisomal disorder. Here we have characterized the genomic structure of the TRIM37 gene, which has 24 exons spanning approximately 109 kb of genomic DNA. Further, we report six novel disease-associated mutations, five of which predict a truncated protein: c.745C>T (p.Gln249X), c.1411C>T (p.Arg471X), c.2056C>T (p.Arg686X), and an 8.6 kb genomic deletion (c.1314+507_1668-207del resulting in p.Arg439fsX4). The sixth mutation (c.965G>T) is the first missense mutation (p.Gly322Val) associated with Mulibrey nanism. It affects the TRAF domain of TRIM37 and results in altered subcellular localization of the mutant TRIM37 protein, further suggesting that it is pathogenic.
authors.affiliation: The Folkhälsan Institute of Genetics and Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: Riikka H
authors.initials: RH
authors.lastname: Hämäläinen
authors.forename: Kristiina
authors.initials: K
authors.lastname: Avela
authors.forename: Julie A
authors.initials: JA
authors.lastname: Lambert
authors.forename: Jukka
authors.initials: J
authors.lastname: Kallijärvi
authors.forename: Wafaa
authors.initials: W
authors.lastname: Eyaid
authors.forename: Jürgen
authors.initials: J
authors.lastname: Gronau
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Ignaszewski
authors.forename: Deborah
authors.initials: D
authors.lastname: McFadden
authors.forename: Giovanni
authors.initials: G
authors.lastname: Sorge
authors.forename: Marita
authors.initials: M
authors.lastname: Lipsanen-Nyman
authors.forename: Anna-Elina
authors.initials: AE
authors.lastname: Lehesjoki
mesh_terms: D000818:Animals; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004392:Dwarfism / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D009154:Mutation; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000032:analysis / Q000235:genetics*; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases
chemical_list: D009687:Nuclear Proteins; D000070584:Tripartite Motif Proteins; C411745:TRIM37 protein, human; D044767:Ubiquitin-Protein Ligases