Germline C1GALT1C1 mutation causes a multisystem chaperonopathy.

Area of Science:

• Biochemistry
• Genetics
• Molecular Biology

Background:

• Chaperonopathies, arising from molecular chaperone gene mutations, are linked to various disorders but not yet to congenital disorders of glycosylation.
• Protein O-glycosylation, a crucial post-translational modification, involves the T-synthase enzyme (C1GALT1) and its chaperone Cosmc (C1GALT1C1).

Purpose of the Study:

• To identify the genetic cause of a novel chaperonopathy characterized by impaired O-glycosylation in two maternal half-brothers.
• To investigate the functional consequences of a specific C1GALT1C1 mutation on T-synthase activity and O-glycan synthesis.

Main Methods:

• Genetic analysis to identify mutations in C1GALT1C1.
• Biochemical assays to measure T-synthase activity and O-glycan structures.
• Cellular studies involving transient transfection to assess protein function.
• Clinical evaluation of patients and family members.

Main Results:

• Two brothers with a hemizygous C1GALT1C1 variant (c.59C>A, p.Ala20Asp; A20D-Cosmc) presented with developmental delay, immunodeficiency, short stature, thrombocytopenia, and acute kidney injury (AKI).
• The A20D-Cosmc mutation led to reduced Cosmc protein expression, consequently decreasing T-synthase activity and causing abnormal O-glycosylation with Tn-antigen expression.
• Affected individuals exhibited high levels of galactose-deficient IgA1, and AKI responded to Eculizumab treatment.

Conclusions:

• The A20D-Cosmc mutation defines a novel O-glycan chaperonopathy, expanding the spectrum of congenital disorders of glycosylation.
• This mutation impairs T-synthase function through reduced Cosmc expression, leading to distinct clinical manifestations.
• The findings highlight the critical role of Cosmc in O-glycosylation and suggest Eculizumab as a potential therapy for associated AKI.