Mutations that impair interaction properties of TRIM32 associated with limb-girdle muscular dystrophy 2H

Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy.
Human Mutation (Impact Factor: 5.05). 02/2008; 29(2):240-7. DOI: 10.1002/humu.20633
Source: PubMed

ABSTRACT TRIM32 belongs to a large family of proteins characterized by a tripartite motif, possibly involved in the ubiquitination process, acting as an E3 ligase. In addition, TRIM32 has six NHL repeats with putative interaction properties. A homozygous mutation at the third NHL repeat (D487N) has been found in patients with limb girdle muscular dystrophy 2H (LGMD2H). This mutation was only identified in the inbred Manitoba Hutterite or their descendants. Interestingly, a mutation in the B-box domain of TRIM32 cosegregates with Bardet-Biedl syndrome type 11 (BBS11). The signs of BBS11 include obesity, pigmentary and retinal malformations, diabetes, polydactyly, and no muscular dystrophy, suggesting an alternative disease mechanism. We aim to ascertain whether D487N is the only pathological LGMD2H allele, limited to Hutterites. We studied the TRIM32 gene in 310 LGMD patients with no mutations at the other known loci. We identified four patients with novel mutated alleles. Two mutations were homozygous and missing in controls. These mutations also clustered at the NHL domain, suggesting that a specific (interaction) property might be abolished in LGMD2H patients. No mutations were found at the B-box region where the BBS11 mutation is found. We tested TRIM32 and its mutants by yeast-two-hybrid assay, developing an interaction test to validate mutations. All LGMD2H mutants, but not the BBS11, lost their ability to self-interact. The interaction of TRIM32 mutants with E2N, a protein involved in the ubiquitination process, was similarly impaired. In conclusion, the mutations here reported may cause muscular dystrophy by affecting the interaction properties of TRIM32.

Download full-text


Available from: Michela Palmieri, Jun 27, 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Limb girdle muscular dystrophy 2H is a rare autosomal recessive muscular dystrophy, clinically highly variable, caused by mutations in the TRIM32 gene. Here we describe a 35-years-old who experienced progressive muscle weakness. The muscle biopsy revealed an unspecific pattern of atrophic and hypertrophic fibers; the immunohistochemistry for several proteins was normal. Comparative genomic hybridization (CGH) analysis showed a heterozygous deletion of the entire TRIM32 gene. On the other allele we identified the R316X nonsense mutation. The genetic diagnosis of LGMD2H in this case was reached by using a novel high throughput diagnostic tool.
    Neuromuscular Disorders 03/2013; 23(6). DOI:10.1016/j.nmd.2013.02.003 · 3.13 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Bardet-Biedl Syndrome (BBS) is a genetically and clinically heterogeneous disorder clinically characterized by obesity, mental retardation, dysphormic extremities (syndactyly, brachydactyly or polydactyly), retinal dystrophy or pigmentary retinopathy, hypogonadism and kidney structural abnormalities or functional impairment. Till now, 14 genes have been identified for BBS on different chromosomes, that is, 11q13 (BBS1), 16q21 (BBS2), 3p12 (BBS3), 15q22 (BBS4), 2q31 (BBS5), 20p12 (BBS6), 4q27 (BBS7), 14q32.11 (BBS8), 7p14 (BBS9), 12q21.2 (BBS10), 9q33.1 (BBS11), 4q27 (BBS12), 17q23 (BBS13), and 12q21.3 (BBS14). Genetic and mutational analysis has indicated that a combination of 3 mutant alleles at two loci is necessary for pathogenesity of BBS. Mutations in BBS genes have impact on different pathways. This study is helpful in generating the databank of disease related mutations and in controlling the disease by understanding the pathogenesis of disease.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In 2005 the commonality of sarcotubular myopathy (STM) and limb girdle muscular dystrophy type 2H (LGMD2H) was demonstrated, as both are caused by the p D487N missense mutation in TRIM32 originally found in the Manitoba Hutterite population. Recently, three novel homozygous TRIM32 mutations have been described in LGMD patients. Here we describe a three generation Swedish family clinically presenting with limb girdle muscular weakness and histological features of a microvacuolar myopathy. The two index patients were compound heterozygotes for a frameshift mutation in TRIM32 (c.1560delC ) and a 30 kb intragenic deletion, encompassing parts of intron 1 and the entire exon 2 of TRIM32. In these patients, no full-length or truncated TRIM32 could be detected. Interestingly, heterozygous family members carrying only one mutation showed mild clinical symptoms and vacuolar changes in muscle. In our family, the phenotype encompasses additionally a mild demyelinating polyneuropathic syndrome. Thus STM and LGMD2H are the result of loss of function mutations that can be either deletions or missense mutations.
    Human Mutation 07/2009; 30(9):E831-44. DOI:10.1002/humu.21063 · 5.05 Impact Factor