21 October 2021

Alex Garanto, Melissa Bärenfänger, Mirian Janssen, and Dirk Lefeber (Theme Metabolic Disorders & Theme Disorders of Movement) together with international colleagues have recently published a new study in the American Journal of Human Genetics identifying a surprisingly dominant genetic cause underlying type I congenital defect of glycosylation with neuromusculoskeletal phenotypes.

Congenital disorders of glycosylation (CDGs) form a group of neurometabolic diseases characterized by hypoglycosylation of proteins. They generally show autosomal recessive inheritance. In this work, 16 individuals from nine families were identified with inherited or de novo heterozygous missense variants in STT3A. STT3A encodes the catalytic subunit of the  oligosaccharyltransferase (OST) complex, essential for transfer of glycans to proteins in the Endoplasmic Reticulum.

Affected individuals presented with variable intellectual disability, skeletal anomalies, short stature, and increased muscle tone and muscle cramps. Modeling of the variants in the 3D structure of the OST complex indicated that all variants are located in the catalytic site of STT3A, suggesting a direct mechanistic link to the transfer of oligosaccharides onto nascent glycoproteins. Expression of STT3A at mRNA and steady-state protein level in fibroblasts was normal, while glycosylation was abnormal.

In contrast, previously reported autosomal recessive mutations in STT3A are located outside the catalytic domain and result in lower STT3A expression.  In S. cerevisiae, expression of STT3 containing variants induced defective glycosylation of carboxypeptidase Y in a wild-type yeast strain and expression of the same mutants in the STT3 hypomorphic stt3-7 yeast strain worsened the already observed glycosylation defect.

These data support a dominant pathomechanism, in which mutated STT3A protein variants are stably included in the OST complex, thereby resulting in a glycosylation defect. This study describes a first dominant form of CDG.



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