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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
- 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.
- Subjects :
- Male
Iduronic Acid
10039 Institute of Medical Genetics
Biopsy
Developmental Disabilities
Iduronic acid
Kidney
Corpus Callosum
Glycosaminoglycan
Extracellular matrix
chemistry.chemical_compound
Sulfation
Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14]
Child
Extracellular Signal-Regulated MAP Kinases
Genetics (clinical)
0303 health sciences
030302 biochemistry & molecular biology
Syndrome
Heparin
Heparan sulfate
Extracellular Matrix
Pedigree
Phenotype
Child, Preschool
Female
Sulfotransferases
medicine.drug
medicine.medical_specialty
Adolescent
610 Medicine & health
Biology
Article
Bone and Bones
03 medical and health sciences
Internal medicine
Genetics
medicine
Humans
Alleles
030304 developmental biology
Family Health
Corpus Callosum Agenesis
Infant, Newborn
Genetic Variation
Fibroblasts
3'-Phosphoadenosine-5'-phosphosulfate
Endocrinology
chemistry
Urogenital Abnormalities
whole-exome sequencing, syndrome, iduronic acid, glycosaminoglycan, paxillin2-O-sulfate, 3’-phosphoadenosine 5’-phosphosulfate, extracellular matrix
570 Life sciences
biology
Heparitin Sulfate
Subjects
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