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Bi-allelic Pathogenic Variants in HS2ST1 Cause a Syndrome Characterized by Developmental Delay and Corpus Callosum, Skeletal, and Renal Abnormalities

Bi-allelic Pathogenic Variants in HS2ST1 Cause a Syndrome Characterized by Developmental Delay and Corpus Callosum, Skeletal, and Renal Abnormalities

Authors :
Katharina Steindl
Peter Meinecke
Catherine L.R. Merry
Leonie von Elsner
Petra J. G. Zwijnenburg
Kerstin Kutsche
Marjan M. Weiss
Anita Rauch
Malik Alawi
Pauline E. Schneeberger
Emma L. Barker
Iris Marquardt
Pascal Joset
University of Zurich
Human genetics
ACS - Atherosclerosis & ischemic syndromes
Amsterdam Reproduction & Development (AR&D)
Source :
Schneeberger, P E, von Elsner, L, Barker, E L, Meinecke, P, Marquardt, I, Alawi, M, Steindl, K, Joset, P, Rauch, A, Zwijnenburg, P J G, Weiss, M M, Merry, C L R & Kutsche, K 2020, ' Bi-allelic Pathogenic Variants in HS2ST1 Cause a Syndrome Characterized by Developmental Delay and Corpus Callosum, Skeletal, and Renal Abnormalities ', American journal of human genetics, vol. 107, no. 6, pp. 1044-1061 . https://doi.org/10.1016/j.ajhg.2020.10.007, American Journal of Human Genetics, 107, 6, pp. 1044-61, Am J Hum Genet, American journal of human genetics, 107(6), 1044-1061. Cell Press, American Journal of Human Genetics, 107, 1044-61
Publication Year :
2020

Abstract

Heparan sulfate belongs to the group of glycosaminoglycans (GAGs), highly sulphated linear polysaccharides. Heparan sulfate 2-O-sulfotransferase 1 (HS2ST1) is one of several specialized enzymes required for heparan sulfate synthesis and catalyzes the transfer of the sulfate groups to the sugar moiety of heparan sulfate. We report biallelic pathogenic variants in the HS2ST1 gene in four individuals from three unrelated families. Affected individuals showed facial dysmorphism with coarse face, upslanted palpebral fissures, broad nasal tip, and wide mouth, developmental delay and/or intellectual disability, corpus callosum agenesis or hypoplasia, flexion contractures, brachydactyly of hands and feet with broad fingertips and toes, and uni- or bilateral renal agenesis in three individuals. HS2ST1 variants cause a reduction in HS2ST1 mRNA and decreased or absent heparan sulfate 2-O-sulfotransferase 1 in two of three fibroblast cell lines derived from affected individuals. The heparan sulfate synthesized by the individual 1 cell line lacks 2-O-sulfated domains but had an increase in N- and 6-O-sulfated domains demonstrating functional impairment of the HS2ST1. As heparan sulfate modulates FGF-mediated signaling, we found a significantly decreased activation of the MAP kinases ERK1/2 in FGF-2-stimulated cell lines of affected individuals that could be restored by addition of heparin, a GAG similar to heparan sulfate. Focal adhesions in FGF-2-stimulated fibroblasts of affected individuals showed an increased length and concentrated at the cell periphery. Our data demonstrate that a heparan sulfate synthesis deficit causes a novel recognizable syndrome and emphasize a role for 2-O-sulfated heparan sulfate in human neuronal, skeletal and renal development.

Details

Language :
English
ISSN :
00029297 and 15376605
Database :
OpenAIRE
Journal :
Schneeberger, P E, von Elsner, L, Barker, E L, Meinecke, P, Marquardt, I, Alawi, M, Steindl, K, Joset, P, Rauch, A, Zwijnenburg, P J G, Weiss, M M, Merry, C L R & Kutsche, K 2020, ' Bi-allelic Pathogenic Variants in HS2ST1 Cause a Syndrome Characterized by Developmental Delay and Corpus Callosum, Skeletal, and Renal Abnormalities ', American journal of human genetics, vol. 107, no. 6, pp. 1044-1061 . https://doi.org/10.1016/j.ajhg.2020.10.007, American Journal of Human Genetics, 107, 6, pp. 1044-61, Am J Hum Genet, American journal of human genetics, 107(6), 1044-1061. Cell Press, American Journal of Human Genetics, 107, 1044-61
Accession number :
edsair.doi.dedup.....d800e7e4919d085cffeabc2cb0fc1024
Full Text :
https://doi.org/10.1016/j.ajhg.2020.10.007