Germline C1GALT1C1 mutation causes a multisystem chaperonopathy

Abstract

Mutations in genes encoding molecular chaperones can lead to chaperonopathies, but none have so far been identified causing congenital disorders of glycosylation. Here we identified two maternal half-brothers with a novel chaperonopathy, causing impaired protein O-glycosylation. The patients have a decreased activity of T-synthase ( C1GALT1 ), an enzyme that exclusively synthesizes the T-antigen, a ubiquitous O-glycan core structure and precursor for all extended O-glycans. The T-synthase function is dependent on its specific molecular chaperone Cosmc, which is encoded by X-chromosomal C1GALT1C1 . Both patients carry the hemizygous variant c.59C>A (p.Ala20Asp; A20D-Cosmc) in C1GALT1C1 . They exhibit developmental delay, immunodeficiency, short stature, thrombocytopenia, and acute kidney injury (AKI) resembling atypical hemolytic uremic syndrome. Their heterozygous mother and maternal grandmother show an attenuated phenotype with skewed X-inactivation in blood. AKI in the male patients proved fully responsive to treatment with the complement inhibitor Eculizumab. This germline variant occurs within the transmembrane domain of Cosmc, resulting in dramatically reduced expression of the Cosmc protein. Although A20D-Cosmc is functional, its decreased expression, though in a cell or tissue-specific manner, causes a large reduction of T-synthase protein and activity, which accordingly leads to expression of varied amounts of pathological Tn-antigen (GalNAcα1-O-Ser/Thr/Tyr) on multiple glycoproteins. Transient transfection of patient lymphoblastoid cells with wild-type C1GALT1C1 partially rescued the T-synthase and glycosylation defect. Interestingly, all four affected individuals have high levels of galactose-deficient IgA1 in sera. These results demonstrate that the A20D-Cosmc mutation defines a novel O-glycan chaperonopathy and causes the altered O-glycosylation status in these patients.

O-GalNAc glycans enrich in white matter tracts and regulate nodes of Ranvier

“…GALNT2 mutations in humans cause a CDG presenting with severe neuropsychiatric symptoms including intellectual disability, seizures, and structural abnormalities, and was mirrored in rodent models of Galnt2 mutation 32 . Changes in Cosmc/T-synthase levels have been reported in Alzheimer’s disease 33 and our group in collaboration with others recently described an X-linked CDG including intellectual disability caused by COSMC ( C1GALT1C1 ) mutation in human male carriers 34 .…”

“…A functional role of O-glycans in the human brain is supported by our recent report of the Cosmc -CDG patients who exhibit neurologic abnormalities 34 . Our identification of this modification on numerous synaptic and cell adhesion molecules, in particular each of the brain-expressed lecticans, canonical carriers of proteoglycans, suggests a fundamental role in brain development and function.…”

“…Based on this pattern we predicted a large loss of extended O-glycans in Cosmc f/y Syn1-Cre + conditional knockouts ( Cosmc Syn1-cKO ) and a narrow loss in Cosmc f/y Gfap-Cre + conditional knockouts ( Cosmc Gfap-cKO ). As Cosmc is an X-linked gene with an associated X-linked disorder 34 , this breeding strategy produced wild-type and knock-out males as well as wild-type and mosaic females.…”

“…Previous studies of Cosmc deletion have leveraged mosaic females in the setting where global deletion in males was lethal or the phenotype was too severe, though this was not the case in our brain Cosmc cKO lines as both hemizygous knockout males and mosaic females were grossly normal. Further, recent studies reveal that COSMC -CDG is an X-linked condition primarily affecting males 34 . Thus, while a limitation of our study is focusing on male mice to leverage the genetic vulnerability and simplicity of O-GalNAc inhibition, future studies targeting O-glycans in females are warranted.…”

A Versatile One-Step Enzymatic Strategy for Efficient Imaging and Mapping of Tumor-Associated Tn Antigen

“…T-synthase is an essential glycotransferase which targets the Tn antigen to synthesize the TF antigen, a fundamental core structure and precursor for mucin-type O-glycans . Glycotransferases with relaxed donor specificity are the key points for chemoenzymatic labeling methods .…”