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TRIM32
tripartite motif containing 32
TRIM32 is located on the long (q) arm of chromosome 9, at band 9q33.1. Arm ratio per GRCh38 - banding schematic.
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Overview
TRIM32 (tripartite motif containing 32) encodes a member of the TRIM protein family, which are E3 ubiquitin ligases responsible for attaching ubiquitin tags to target proteins. This marking process directs proteins either for degradation or alters their cellular activity. The TRIM32 protein is particularly important in skeletal muscle, where it helps maintain the balance between protein synthesis and breakdown necessary for muscle fibre integrity. Pathogenic variants in TRIM32 are inherited in an autosomal recessive pattern, meaning two altered copies are required to cause disease. The gene is located on chromosome 9 at position 9q33.1 and produces a 653-amino-acid protein.
What the gene does
The TRIM32 protein functions as an E3 ubiquitin ligase, catalysing the transfer of ubiquitin molecules onto specific target proteins within cells. This ubiquitination process serves as a molecular signal that can trigger protein degradation through the proteasome pathway or modify protein activity and localisation. In muscle tissue, TRIM32 regulates proteins involved in muscle differentiation and maintenance, ensuring proper muscle cell development and function. The protein also participates in controlling cell division and has been implicated in neuronal development and function. By selectively marking proteins for breakdown, TRIM32 helps cells respond to changing conditions and maintain protein quality control, preventing the accumulation of damaged or misfolded proteins that could interfere with cellular processes.
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Chromosome location
TRIM32 is located on the long arm of chromosome 9 at cytogenetic band 9q33.1. This chromosomal region contains multiple genes, and the TRIM32 locus spans approximately 14 kilobases of genomic DNA. The gene comprises multiple exons that are transcribed and spliced together to produce the messenger RNA template for protein synthesis.
Protein structure
The TRIM32 protein contains characteristic tripartite motif domains at its N-terminus, including a RING-type zinc finger domain (amino acids 20-65) that mediates the ubiquitin ligase activity, followed by a B box-type zinc finger domain (amino acids 103-133) and a coiled coil region (amino acids 138-197) that facilitates protein-protein interactions. The C-terminal half of the protein features five NHL repeats: NHL 1 (amino acids 358-401), NHL 2 (amino acids 415-458), NHL 3 (amino acids 459-499), NHL 4 (amino acids 562-605), and NHL 5 (amino acids 606-646). These NHL domains form a beta-propeller structure that recognises and binds specific target proteins, determining substrate specificity for the ubiquitination reaction.
Key variants
Pathogenic variants in TRIM32 typically result in loss of protein function, either through disrupting the catalytic RING domain or altering the NHL repeats that recognise target proteins. Missense variants that change single amino acids are commonly observed, particularly affecting the NHL repeat region. These alterations can impair the protein's ability to bind its normal targets or reduce its ubiquitin ligase activity, leading to disrupted protein homeostasis in affected tissues.
No pathogenic or likely-pathogenic ClinVar variants recorded yet for this gene.
Associated conditions
Biallelic pathogenic variants in TRIM32 cause limb-girdle muscular dystrophy type 2H (LGMD2H), characterised by progressive weakness of the shoulder and hip girdle muscles typically beginning in adolescence or early adulthood. Some variants have also been associated with Bardet-Biedl syndrome-like features or sarcotubular myopathy, conditions affecting multiple organ systems. The severity and specific features can vary depending on which variants are present and how severely they affect protein function.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic TRIM32 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
TRIM32 is included in NHS Genomic Medicine Service gene panels for diagnostic testing. The gene appears on the DDG2P panel with a green rating, indicating definitive evidence for its role in developmental disorders. It is also listed on the "Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies" panel (R82) with green classification, reflecting strong clinical validity for testing in patients with these muscle conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does autosomal recessive inheritance mean for TRIM32 variants?
Autosomal recessive inheritance means a person must inherit two altered copies of TRIM32 (one from each parent) to develop associated conditions. Individuals with one altered copy are carriers and typically do not have symptoms but can pass the variant to their children.
How does TRIM32 protein dysfunction lead to muscle disease?
Loss of TRIM32 function disrupts the controlled breakdown of target proteins in muscle cells, leading to accumulation of proteins that interfere with muscle fibre structure and function. This imbalance gradually damages muscle tissue, resulting in progressive weakness characteristic of muscular dystrophy.
Are all TRIM32 variants associated with the same condition?
Different TRIM32 variants can lead to varying clinical presentations, from isolated muscle weakness to more complex syndromes affecting multiple systems. The specific location and nature of variants within the gene influence which cellular functions are most severely disrupted and therefore which symptoms predominate.