A novel splice site mutation in theTRIM37 gene causes mulibrey nanism in a Turkish family with phenotypic heterogeneity

Abstract

Mulibrey nanism (muscle-liver-brain-eye nanism; MUL) is an autosomal recessively transmitted disease characterized by severe growth delays of prenatal onset caused by mutations in the TRIM37 gene. Recent studies on the subcellular localization revealed that the TRIM37 (KIAA0898) protein is located in peroxisomes. Therefore, MUL has been classified as a new peroxisomal disorder. Up to now, four mutations have been reported, all of which lead to frameshifts and truncated proteins. In this study, mutation screening was performed for the coding region of the TRIM37 gene in a Turkish family by means of RT-PCR and direct cDNA sequencing. We have identified a novel mutation resulting in a frameshift cosegregating within the family. Finally, we report on the presence of novel splice variants observed in lymphoblastoid cells and muscle tissue of normal subjects and patients.

Novel mutations in theTRIM37gene in Mulibrey Nanism

“…The eleven TRIM37 mutations are distributed evenly from exon 7 to exon 19 with no evident mutational hotspots. Concordant with the previous findings [Avela et al, 2000;Jagiello et al, 2003) five of the new mutations result in premature translation termination codons either through nonsense or frameshift mutations. Thus, these mutations are predicted to cause a truncated protein, likely making it nonfunctional or to be destined to RNA-degradation by nonsense mediated decay [Mendell and Dietz, 2001].…”

Tissue expression of the mulibrey nanism-associated Trim37 protein in embryonic and adult mouse tissues

“…Other common features include J-shaped sella turcica, yellowish dots in the ocular fundi, slight muscular weakness, cutaneous naevi flammei, and enlargement of cerebral ventricles (Perheentupa et al 1973;Lipsanen-Nyman et al 2003;Karlberg et al 2004). Nine disease-associated truncating mutations and two missense mutations in the TRIM37 gene have been identified (Avela et al 2000;Jagiello et al 2003;Ha¨ma¨la¨inen et al 2004;Kallija¨rvi et al 2005). Several alternatively spliced variants of TRIM37 are present in the human transcriptome.…”

TRIM37 defective in mulibrey nanism is a novel RING finger ubiquitin E3 ligase

“…The fulllength TRIM37 co-localizes with peroxisomal markers in cultured cells and, by immunofluorescence analysis, endogenous TRIM37 immunoreactivity is detected in peroxisomes in several cell lines [7]. Ten nonsense mutations and one missense mutation (p.Gly322Val) in the TRIM37 gene have been described in mulibrey nanism patients [9,11,12]. The most common mulibrey nanism-associated TRIM37 mutation, the Finnish founder mutation, is a c.493-2A > G transition in a 3 ¶ splice site resulting in aberrant splicing and a 5-base pair deletion in the cDNA [9].…”