Novel mutations in theTRIM37gene 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.

Using extended pedigrees to identify novel autism spectrum disorder (ASD) candidate genes

“…Moreover, different isoforms of DLC1 have been observed to cause multiple phenotypes in mice (Sabbir et al 2010), and have previously been described in association with ASD ). Another gene is TRIM37, notable for its involvement in developmental patterning, and its association with 'mulibrey nanism', an autosomal recessive disorder of muscle, liver, brain and eye development (Hämäläinen et al 2004). There are, however, no data supporting a role for this gene in ASD, intellectual development or any other mental disorders.…”

Gynecological tumors in Mulibrey nanism and role for RING finger protein TRIM37 in the pathogenesis of ovarian fibrothecomas

“…Mulibrey nanism is caused by mutations in the TRIM37 gene on chromosome 17q22-23. [5][6][7] It codes for a protein belonging to the TRIM (TRIpartite Motif; previously designated RBCC for RING-Bbox-Coiled-coil) protein family, members of which are often involved in developmental regulation and oncogenesis. 6 The wild-type TRIM37 protein localizes to peroxisomes in cultured human and rodent cells 8 and possesses ubiquitin E3 ligase activity.…”

“…6,7,[9][10][11][12] The recessive nature of the disorder and the fact that all but four of the disease-associated mutations are truncating suggest a loss-of-function modality underlying the pathogenesis of Mulibrey nanism. The physiological function of TRIM37 and the exact molecular mechanisms leading to Mulibrey nanism are unknown.…”

TRIMming down tumor suppressors in breast cancer

“…A number of truncating frame-shift mutations in TRIM37 have been identified in individuals with the disease. 5,6 In most cases, the truncated TRIM37 protein is predicted to retain an intact and likely functional RING domain, raising the possibility that the oncogenic activity of TRIM37 might contribute to the high frequency of tumors associated with mulibrey nanism. 7 However, whether aberrant TRIM37 E3 ubiquitin ligase activity is an underlying cause of the growth defects observed in mulibrey nanism is an interesting question that merits further study.…”