TRIM32 – Bardet-Biedl Syndrome Type 11

TRIM32 (HGNC:16380) encodes an E3 ubiquitin ligase with a tripartite motif and C-terminal NHL repeats, broadly expressed in muscle and neural tissues. Bardet-Biedl syndrome type 11 (BBS11; MONDO:0014439) is an autosomal recessive ciliopathy characterized by obesity, pigmentary retinopathy, diabetes, polydactyly, and normal muscle histology, implicating a distinct mechanism from muscular dystrophy. TRIM32 and BBS11 association has been described in a founder population of Manitoba Hutterites.

In a cohort of 310 limb-girdle muscular dystrophy patients wild-type for known loci, a B-box domain variant c.388C>T (p.Pro130Ser) was identified homozygously in multiple affected individuals from a single kindred and was absent in controls, cosegregating with obesity, pigmentary retinopathy, diabetes, and polydactyly but not muscular dystrophy. Limited recurrence of this allele supports an autosomal recessive inheritance for BBS11 (PMID:17994549).

Functional assays comparing LGMD2H-associated NHL mutations with the BBS11 p.Pro130Ser allele demonstrated that the latter retains normal self-interaction and E3 ligase activity toward substrates such as dysbindin, unlike D487N and R394H mutants that abrogate ubiquitination (PMID:19349376). This indicates that BBS11 arises from perturbation of TRIM32 functions distinct from those underlying muscle pathology.

Although the precise pathogenic mechanism for BBS11 remains undefined, the allele-specific retention of enzymatic function suggests that p.Pro130Ser may alter non-canonical substrate interactions or subcellular localization. Further studies are needed to elucidate how B-box perturbation drives the pleiotropic features of BBS11.

Genetic testing for TRIM32 should include analysis of B-box variants in patients presenting with BBS11 phenotypes, as differentiation from LGMD2H has direct implications for prognosis and management. The c.388C>T (p.Pro130Ser) allele serves as a diagnostic marker in founder populations and informs carrier screening.

Key take-home: Homozygous TRIM32 B-box variant c.388C>T (p.Pro130Ser) causes autosomal recessive Bardet-Biedl syndrome type 11 via a distinct molecular mechanism from limb-girdle muscular dystrophy.

References

• Human mutation | 2008 | Mutations that impair interaction properties of TRIM32 associated with limb-girdle muscular dystrophy 2H. PMID:17994549
• Human molecular genetics | 2009 | TRIM32 is an E3 ubiquitin ligase for dysbindin. PMID:19349376

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