Disease relevance of TRIM37

• Mulibrey nanism is a rare growth disorder of prenatal onset caused by mutations in the TRIM37 gene, which encodes a RING-B-box-coiled-coil protein [1].
• The TRIM37 gene encodes a peroxisomal RING-B-box-coiled-coil protein: classification of mulibrey nanism as a new peroxisomal disorder [1].
• Mutations in TRIM37 underlie mulibrey nanism, a rare autosomal recessively inherited disorder with severe growth failure of prenatal onset, constrictive pericardium, hepatomegaly and characteristic dysmorphic features [2].
• Wilms' tumor and novel TRIM37 mutations in an Australian patient with mulibrey nanism [3].
• Mutations in the TRIM37 gene underlie mulibrey nanism (muscle-liver-brain-eye nanism), a rare monogenic developmental disorder characterized by severe growth failure, characteristic dysmorphic features, cardiopathy, failure of sexual maturation, and metabolic syndrome [4].

High impact information on TRIM37

• We previously assigned MUL to chromosome 17q22-q23 and constructed a physical contig over the critical MUL region [5].
• MUL is ubiquitously expressed and encodes a new member of the RING-B-box-Coiled-coil (RBCC) family of zinc-finger proteins, whose members are involved in diverse cellular functions such as developmental patterning and oncogenesis [5].
• Colocalization of endogenous TRIM37 with peroxisomal markers was observed by double immunofluorescence staining in HepG2 and human intestinal smooth muscle cell lines [1].
• Fibroblasts derived from patients with mulibrey nanism lack C-terminal TRIM37 immunoreactivity but stain normally for both peroxisomal matrix and membrane markers, suggesting apparently normal peroxisome biogenesis in patient fibroblasts [1].
• Assignment of the mulibrey nanism gene to 17q by linkage and linkage-disequilibrium analysis [6].

Chemical compound and disease context of TRIM37

• We evaluated the glucose and lipid metabolism in 65 patients (aged 1.1-55 years) with mulibrey (muscle-liver-brain-eye) nanism (MUL), which is a monogenic disorder with prenatal-onset growth failure and typical clinical characteristics [7].
• Twenty-four patients with metastatic breast cancer that had progressed after high-dose chemotherapy with peripheral blood progenitor cell (PBPC) support were given intramuscular methotrexate in combination with oral UFT (tegafur and uracil) and oral leucovorin (the MUL regimen) [8].

Biological context of TRIM37

• Polyubiquitination was decreased in a mutant protein with disrupted RING domain (Cys35Ser;Cys36Ser) and in the Leu76Pro mutant protein, a disease-associated missense mutation affecting the TRIM domain of TRIM37 [9].
• We here characterised TRIM37 further by mapping the transcription initiation site and promoter region as well as by analysing splice variants [2].
• Here we have characterized the genomic structure of the TRIM37 gene, which has 24 exons spanning approximately 109 kb of genomic DNA [10].
• In the common critical region, the conserved haplotypes were different in MKS and MUL patients [11].
• The results showed a dramatic change in glucose and lipid metabolism with age in MUL subjects [7].

Anatomical context of TRIM37

• These data suggest that TRIM37 expression is regulated by several mechanisms: through nonsense surveillance of non-functional transcripts, as well as through 3'UTR regulatory sequences and/or naturally occurring antisense RNAs especially in testis [2].
• TRIM37 localizes to peroxisomes classifying Mulibrey nanism as a peroxisomal disorder [10].
• We report on 3 patients with Mulibrey nanism (MN), or Perheentupa syndrome: the first 2 sibs from Argentina and a new patient from Spain. All 3 patients had growth failure, short stature, abnormal pigmentary retinal changes, and a J-shaped sella turcica [12].
• Mutations or rearrangements in several B-box family members are associated with human diseases and cancers such as familial Mediterranean fever (FMF), Optiz/BBB syndrome, acute promyelocytic leukemia, mulibrey nanism, and thyroid carcinomas [13].

Other interactions of TRIM37

• Data base searches revealed multiple proteins containing TDs homologous to those found in MUL, USP7, and SPOP throughout eukaryotes, including yeast, protists, plants, invertebrates, and mammals, suggesting that this branch of the TD family arose from an ancient gene [14].
• The TD of MUL also interacted with itself, whereas the TDs of USP7 and SPOP did not self-associate [14].
• Mutations in TRIM37 encoding a tripartite motif (TRIM, RING-B-box-coiled-coil)-family protein underlie mulibrey nanism [9].
• Mulibrey nanism is an autosomal recessive prenatal-onset growth disorder characterized by dysmorphic features, cardiomyopathy, and hepatomegaly [9].
• Mulibrey nanism and Wilms tumor [15].

Analytical, diagnostic and therapeutic context of TRIM37

• 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 [16].
• Immunofluorescence confocal microscopy indicated that MUL localizes to cytosolic bodies, with targeting to these structures mediated by a RBCC tripartite domain within the MUL protein [14].
• Identifying the anomalies specific to MN should help its early diagnosis and treatment [12].
• Growth failure with pericardial constriction. The syndrome of mulibrey nanism [17].
• In conclusion, MUL chemotherapy is active and well tolerated in patients with metastatic breast cancer in progression after high-dose chemotherapy [8].

References