Loss of NDST1 N-sulfotransferase activity is associated with autosomal recessive intellectual disability

Author:

Khosrowabadi Elham1,Mignon-Ravix Cécile2,Riccardi Florence23,Cacciagli Pierre4,Desnous Béatrice5,Sigaudy Sabine6,Milh Mathieu25,Villard Laurent27ORCID,Kjellén Lena1ORCID,Molinari Florence2ORCID

Affiliation:

1. Department of Medical Biochemistry and Microbiology, The Biomedical Center , Husargatan 3, 751 23 Uppsala , Sweden

2. Aix-Marseille Univ, INSERM, MMG , Centre de génétique médicale de Marseille, 27 Bd Jean Moulin, 13385 Marseille Cedex 05 , France

3. Département de Génétique Médicale, Hôpital Ste Musse , 54 Rue Henri Sainte-Claire Deville, 83100 Toulon , France

4. Biological Resource Center, Assistance Publique des Hôpitaux de Marseille , Hôpital Timone Enfants, 264 rue Saint Pierre, 13385 Marseille cedex 05 , France

5. Service de Neuropédiatrie, AP-HM, Hôpital Timone Enfants , 264 rue Saint Pierre, 13385 Marseille cedex 05 , France

6. Service de Génétique Clinique, AP-HM, Hôpital Timone Enfants , 264 rue Saint Pierre, 13385 Marseille cedex 05 , France

7. Département de Génétique Médicale, AP-HM, Hôpital Timone Enfants , 264 rue Saint Pierre, 13385 Marseille cedex 05 , France

Abstract

Abstract Intellectual Disability (ID) is the major cause of handicap, affecting nearly 3% of the general population, and is highly genetically heterogenous with more than a thousand genes involved. Exome sequencing performed in two independent families identified the same missense variant, p.(Gly611Ser), in the NDST1 (N-deacetylase/N-sulfotransferase member 1) gene. This variant had been previously found in ID patients of two other families but has never been functionally characterized. The NDST1 gene encodes a bifunctional enzyme that catalyzes both N-deacetylation and N-sulfation of N-acetyl-glucosamine residues during heparan sulfate (HS) biosynthesis. This step is essential because it influences the downstream enzymatic modifications and thereby determines the overall structure and sulfation degree of the HS polysaccharide chain. To discriminate between a rare polymorphism and a pathogenic variant, we compared the enzymatic properties of wild-type and mutant NDST1 proteins. We found that the p.(Gly611Ser) variant results in a complete loss of N-sulfotransferase activity while the N-deacetylase activity is retained. NDST1 shows the highest and the most homogeneous expression in the human cerebral structures compared to the other members of the NDST gene family. These results indicate that a loss of NDST1 N-sulfation activity is associated with impaired cognitive functions.

Funder

Excellence Initiative of Aix-Marseille University - A*Midex a French

Swedish Cancer Society

Swedish Brain Foundation

Publisher

Oxford University Press (OUP)

Subject

Genetics (clinical),Genetics,Molecular Biology,General Medicine

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3