B4GALT1 – B4GALT1-congenital Disorder of Glycosylation

B4GALT1 encodes β-1,4-galactosyltransferase 1, a glycosyltransferase essential for N-linked glycan maturation. Autosomal recessive mutations in B4GALT1 lead to a congenital disorder of glycosylation (CDG) characterized by multi-system involvement and defective protein galactosylation. Early reports identified three unrelated patients with severe dyslipidemia and glycosylation defects (PMID:31800099).

Inheritance is autosomal recessive, with six total probands reported across two cohorts: three initial cases with hypogalactosylated, hypo-active CETP (cholesteryl ester transfer protein) and three additional patients homozygous for a novel variant in an extended pedigree (PMID:31800099; PMID:32157688).

Segregation analysis in the extended family confirmed co-segregation of the c.61C>T (p.Arg21Trp) variant with disease in four additional affected relatives (PMID:32157688).

Variant spectrum is currently limited to missense changes; the recurrent pathogenic allele c.61C>T (p.Arg21Trp) disrupts the transmembrane domain of B4GALT1. No loss-of-function or deep-intronic variants have been described to date.

Functional studies demonstrate that patients exhibit significantly lowered non-HDL cholesterol and altered HDL particle size due to hypogalactosylated, hypo-active CETP (PMID:31800099). Structural investigations of B4GALT1 underscore critical roles for amino acids in the catalytic and donor-binding loops, supporting a loss-of-function mechanism.

Clinically, affected individuals present with intellectual disability (HP:0001249), pancytopenia (HP:0001871), pulmonary hypertension (HP:0002091), and nephrotic syndrome (HP:0004971), reflecting systemic glycosylation defects.

References

• Journal of inherited metabolic disease • 2020 • Reduced CETP glycosylation and activity in patients with homozygous B4GALT1 mutations. PMID:31800099
• Clinical Genetics • 2020 • B4GALT1-congenital disorders of glycosylation: Expansion of the phenotypic and molecular spectrum and review of the literature. PMID:32157688

Evidence Based Scoring (AI generated)