Mulibrey Nanism, an Autosomal Recessive Syndrome With Pericardial Constriction

Perheentupa, Jaakko; Leisti, Seppo; Autio, S.; Raitta, Christina; Tuuteri, L

doi:10.1016/s0140-6736(73)93193-0

Cited by 54 publications

(41 citation statements)

References 2 publications

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“…Mulibrey nanism (muscle-liver-brain-eye nanism; MIM# 253250) is an autosomal recessive growth disorder [Perheentupa et al, 1973]. It is characterized by prenatal-onset growth failure and heart disease involving constrictive pericarditis and restrictive cardiomyopathy [Lipsanen-Nyman et al, 2003].…”

Section: Introductionmentioning

confidence: 99%

Novel mutations in theTRIM37gene in Mulibrey Nanism

et al. 2004

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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.

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Section: Introductionmentioning

confidence: 99%

Novel mutations in theTRIM37gene in Mulibrey Nanism

et al. 2004

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“…Mulibrey nanism (acronym for muscle-liver-braineye nanism, MUL; MIM# 253250) is a rare disorder characterized by growth delay, triangular face often associated with hydrocephaloid skull, gracility, muscular hypotonia, peculiar voice, enlarged liver, raised venous pressure due to pericardial constriction, and yellowish dots as well as pigment dispersion in the ocular fundi [Perheentupa et al, 1973]. Two-thirds of the patients have cutaneus naevi flammei, one-third have shown cystic dysplasia of the tibia, and almost 4% develop Wilms tumors.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2003

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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.

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“…Mulibrey nanism is an autosomal recessive inherited disorder characterized by prenatal-onset growth failure, distinct craniofacial features, perimyocardial heart disease, insulin resistance and a mainly unaffected psychomotor development. [1][2][3][4] This disorder is enriched in Finland where 88 of the approximately 130 known patients have been diagnosed. Mulibrey nanism is caused by mutations in the TRIM37 gene on chromosome 17q22-23.…”

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confidence: 99%

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

et al. 2009

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Mulibrey nanism is an autosomal recessive growth disorder caused by mutations in the TRIM37 gene encoding a protein of unknown function. More than half of female patients with Mulibrey nanism develop benign mesenchymal tumors of ovarian sex cord-stromal origin. In this work, we characterize the gynecological tumors of female patients with Mulibrey nanism in detail. In addition to tumors of the fibrothecoma group, 18% (4/22) of the patients were observed with epithelial neoplasias, including 2 ovarian adenofibromas, 1 ovarian poorly differentiated adenocarcinoma and 1 endometrial adenocarcinoma. To investigate the possible involvement of TRIM37 alterations in the pathogenesis of sporadic fibrothecomas, we analyzed the TRIM37 cDNA for mutations and alternatively spliced transcripts and TRIM37 expression in fibrothecomas of women without Mulibrey nanism. No mutations in the open-reading frame of TRIM37 were detected. Two alternatively spliced variants were found, one lacking exon 23 and one exon 2. TRIM37del2 was also found in normal ovary but in a proportion of sporadic fibrothecomas, the TRIM37del2:TRIM37 ratio was increased. In normal ovary, TRIM37 was localized in the cytoplasm of stromal cells, especially theca cells surrounding developing follicles. TRIM37 transcript was found in all sporadic fibrothecomas examined, but 80% (20/25) of the tumors showed reduced or absent expression of TRIM37 protein. Allelic loss at the TRIM37 locus (17q22-23) was observed in 6% of sporadic fibrothecomas. Nearly half of the sporadic fibrothecomas showed evidence of CpG promoter methylation, suggesting promoter downregulation as one mechanism of reduced TRIM37 expression. In conclusion, inherited biallelic inactivation of TRIM37 (Mulibrey nanism) predisposes to both mesenchymal and epithelial ovarian tumors and dysregulation of TRIM37 may also be involved in the pathogenesis of sporadic fibrothecomas.

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Mulibrey Nanism, an Autosomal Recessive Syndrome With Pericardial Constriction

Cited by 54 publications

References 2 publications

Novel mutations in theTRIM37gene in Mulibrey Nanism

Novel mutations in theTRIM37gene in Mulibrey Nanism

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

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

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