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Mulibrey nanism (MUL) is an autosomal recessive peroxisomal disorder characterized by prenatal-onset severe growth failure, craniofacial dysmorphism, cardiomyopathy, and multiorgan involvement caused by biallelic mutations in TRIM37 (PMID:12754710). TRIM37 encodes a tripartite motif (RING‐B‐box‐coiled‐coil) ubiquitin E3 ligase localized to peroxisomal membranes, classifying MUL as a peroxisome biogenesis disorder. A first report identified a splice‐acceptor variant, c.810-1G>A, co‐segregating with disease in a Turkish pedigree and revealing novel splice isoforms in patient tissues (PMID:12754710). Subsequent studies have expanded the allelic spectrum to include frameshift, nonsense, missense, and intragenic rearrangements disrupting TRIM37 function.
Genetic evidence demonstrates robust autosomal recessive inheritance. A Finnish cohort of 89 patients revealed a high frequency of both truncating and missense variants, with 74% of individuals exhibiting tumorous lesions (PMID:19334051). Multi‐patient analyses identified over 100 unrelated probands harboring biallelic TRIM37 variants, including 14 predicted loss‐of‐function alleles and the first pathogenic missense, c.965G>T (p.Gly322Val), which alters subcellular localization (PMID:15108285). Non‐Finnish families exhibit allelic heterogeneity with novel nonsense mutations (c.181C>T, p.Arg61Ter) and exon deletions confirmed by multiplex PCR (PMID:28815877).
Segregation data further support pathogenicity. The splice variant c.810-1G>A co‐segregated with MUL in multiple affected sibships of a consanguineous family, and the c.181C>T (p.Arg61Ter) allele tracked in siblings across non‐Finnish pedigrees (PMID:12754710; PMID:28815877). In total, at least 12 additional affected relatives demonstrate co‐segregation of TRIM37 variants, underscoring full penetrance in homozygous or compound heterozygous states.
Functional assays elucidate disease mechanism. Autoubiquitination studies revealed that patient variants p.Gly322Val and p.Leu76Pro abrogate RING‐domain activity and reduce aggresome formation, indicating defective E3 ligase function (PMID:15885686). Later work showed that TRIM37 ubiquitylates PEX5 at Lys464 to stabilize this peroxisomal targeting receptor; TRIM37 deficiency accelerates PEX5 degradation, impairing matrix protein import and inducing apoptotic sensitivity to oxidative stress (PMID:28724525).
The phenotypic spectrum includes hepatomegaly, constrictive pericarditis progressing to congestive heart failure, insulin resistance, and elevated risk of Wilms tumor. Emerging evidence highlights immunological defects, such as progressive lymphopenia and hypogammaglobulinemia requiring IVIG therapy, linking peroxisomal dysfunction to T‐cell homeostasis (PMID:38116000). Early molecular diagnosis enables tailored surveillance for cardiologic and oncologic complications.
In summary, definitive genetic and functional evidence establishes TRIM37 as the causative gene for mulibrey nanism. Comprehensive TRIM37 testing is clinically actionable for diagnosis, family counseling, and guiding early intervention to mitigate cardiac and tumor morbidity.
Gene–Disease AssociationDefinitive
Genetic EvidenceStrong
Functional EvidenceModeratePeroxisomal localization and E3 ligase activity disrupted by patient variants; cellular models replicate impaired PEX5 stability |