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COLGALT1 encodes collagen β1‐O galactosyltransferase 1, which mediates post‐translational galactosylation of type IV collagen in cerebral vessel basement membranes. Brain small vessel disease 3 (BSVD3) [MONDO:0100105] is an autosomal recessive leukovasculopathy presenting prenatally with porencephaly and postnatally with refractory epilepsy, progressive hydrocephalus, severe developmental delay, and spastic quadriplegia.
To date, three unrelated probands have been reported with biallelic pathogenic COLGALT1 variants: two compound heterozygotes with missense and frameshift alleles and one homozygote for a canonical splice site variant c.625-2A>C^(PMID:33709034)(PMID:30412317). All patients share severe porencephaly and spastic quadriplegia. Parental segregation in nuclear families confirms recessive inheritance but no extended segregation beyond parents has been documented.
The variant spectrum includes canonical splice site, missense (p.Leu151Arg, p.Ala154Pro, p.Gly377Arg), and frameshift (p.Glu366ArgfsTer15) alleles predicted to disrupt ColGalT1 folding or stability. Functional studies demonstrated that p.Leu151Arg and p.Ala154Pro destabilize protein structure on three-dimensional modeling, abolishing galactosyltransferase activity. Western blot and enzymatic assays showed undetectable ColGalT1 expression/activity, and RNA interference with rescue experiments confirmed that mutant COLGALT1 fails to restore COL4A1 secretion to the extracellular matrix^(PMID:30412317).
These concordant genetic and experimental data support a loss-of-function mechanism for COLGALT1 in BSVD3. No conflicting reports have been published. Collectively, the evidence meets ClinGen criteria for a strong gene–disease association. Key Take-Home: Biallelic COLGALT1 variants cause BSVD3 via impaired collagen modification, justifying inclusion of COLGALT1 in diagnostic panels for cerebral small vessel disorders.
Gene–Disease AssociationStrongThree unrelated probands with biallelic splice, missense, and frameshift variants^(PMID:33709034)(PMID:30412317); concordant in vitro functional assays^(PMID:30412317) Genetic EvidenceModerate3 probands from 3 unrelated families with biallelic canonical splice or missense and frameshift variants, AR inheritance; limited segregation Functional EvidenceStrongStructural modeling, enzymatic assays, RNA interference and rescue experiments demonstrate loss-of-function mechanism^(PMID:30412317) |