TY - JOUR
T1 - Active site variants in STT3A cause a dominant type I congenital disorder of glycosylation with neuromusculoskeletal findings
AU - Wilson, Matthew P.
AU - Garanto, Alejandro
AU - Pinto e Vairo, Filippo
AU - Ng, Bobby G.
AU - Ranatunga, Wasantha K.
AU - Ventouratou, Marina
AU - Baerenfaenger, Melissa
AU - Huijben, Karin
AU - Thiel, Christian
AU - Ashikov, Angel
AU - Keldermans, Liesbeth
AU - Souche, Erika
AU - Vuillaumier-Barrot, Sandrine
AU - Dupré, Thierry
AU - Michelakakis, Helen
AU - Fiumara, Agata
AU - Pitt, James
AU - White, Susan M.
AU - Lim, Sze Chern
AU - Gallacher, Lyndon
AU - Peters, Heidi
AU - Rymen, Daisy
AU - Witters, Peter
AU - Ribes, Antonia
AU - Morales-Romero, Blai
AU - Rodríguez-Palmero, Agustí
AU - Ballhausen, Diana
AU - de Lonlay, Pascale
AU - Barone, Rita
AU - Janssen, Mirian C.H.
AU - Jaeken, Jaak
AU - Freeze, Hudson H.
AU - Matthijs, Gert
AU - Morava, Eva
AU - Lefeber, Dirk J.
N1 - Publisher Copyright:
© 2021 American Society of Human Genetics
PY - 2021/11/4
Y1 - 2021/11/4
N2 - Congenital disorders of glycosylation (CDGs) form a group of rare diseases characterized by hypoglycosylation. We here report the identification of 16 individuals from nine families who have either inherited or de novo heterozygous missense variants in STT3A, leading to an autosomal-dominant CDG. STT3A encodes the catalytic subunit of the STT3A-containing oligosaccharyltransferase (OST) complex, essential for protein N-glycosylation. Affected individuals presented with variable skeletal anomalies, short stature, macrocephaly, and dysmorphic features; half had intellectual disability. Additional features included 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. Indeed, expression of STT3A at mRNA and steady-state protein level in fibroblasts was normal, while glycosylation was abnormal. In S. cerevisiae, expression of STT3 containing variants homologous to those in affected individuals 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 underlying the glycosylation defect. Recessive mutations in STT3A have previously been described to lead to a CDG. We present here a dominant form of STT3A-CDG that, because of the presence of abnormal transferrin glycoforms, is unusual among dominant type I CDGs.
AB - Congenital disorders of glycosylation (CDGs) form a group of rare diseases characterized by hypoglycosylation. We here report the identification of 16 individuals from nine families who have either inherited or de novo heterozygous missense variants in STT3A, leading to an autosomal-dominant CDG. STT3A encodes the catalytic subunit of the STT3A-containing oligosaccharyltransferase (OST) complex, essential for protein N-glycosylation. Affected individuals presented with variable skeletal anomalies, short stature, macrocephaly, and dysmorphic features; half had intellectual disability. Additional features included 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. Indeed, expression of STT3A at mRNA and steady-state protein level in fibroblasts was normal, while glycosylation was abnormal. In S. cerevisiae, expression of STT3 containing variants homologous to those in affected individuals 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 underlying the glycosylation defect. Recessive mutations in STT3A have previously been described to lead to a CDG. We present here a dominant form of STT3A-CDG that, because of the presence of abnormal transferrin glycoforms, is unusual among dominant type I CDGs.
KW - congenital disorders of glycosylation
KW - dominant inheritance
KW - glycosylation
KW - oligosaccharyltransferase complex
UR - http://www.scopus.com/inward/record.url?scp=85118510371&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85118510371&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2021.09.012
DO - 10.1016/j.ajhg.2021.09.012
M3 - Article
C2 - 34653363
AN - SCOPUS:85118510371
SN - 0002-9297
VL - 108
SP - 2130
EP - 2144
JO - American journal of human genetics
JF - American journal of human genetics
IS - 11
ER -