Mutations in SLC35A3 cause autism spectrum disorder, epilepsy and arthrogryposis (original) (raw)

Mutations in SLC35A3 cause autism spectrum disorder, epilepsy and arthrogryposis

Simon Edvardson1,
Angel Ashikov2,
Chaim Jalas3,
Luisa Sturiale4,
Avraham Shaag1,
Anastasia Fedick5,
Nathan R Treff5,6,
Domenico Garozzo4,
Rita Gerardy-Schahn2,
Orly Elpeleg1
1Monique and Jacques Roboh, Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
2Institute for Cellular Chemistry, Hannover Medical School, Hannover, Germany
3Bonei Olam Center for Rare Jewish Genetic Disorders, Brooklyn, New York, USA
4CNR, Institute of Chemistry and Technology of Polymers, Section of Catania, Italy
5Department of Molecular Genetics, Microbiology, and Immunology, UMDNJ-Robert Wood Johnson Medical School, Piscataway, New Jersey, USA
6Reproductive Medicine Associates of New Jersey, Morristown, New Jersey, USA
Correspondence to Professor Orly Elpeleg, Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center, Ein karem, Jerusalem 91120, Israel; Elpeleg{at}Hadassah.org.il and Professor Rita Gerardy-Schahn, Institute for Cellular Chemistry, Hannover Medical School, 30625 Hannover, Germany; Gerardy-Schahn.Rita{at}mh-hannover.de

Abstract

Background The heritability of autism spectrum disorder is currently estimated at 55%. Identification of the molecular basis of patients with syndromic autism extends our understanding of the pathogenesis of autism in general. The objective of this study was to find the gene mutated in eight patients from a large kindred, who suffered from autism spectrum disorder, arthrogryposis and epilepsy.

Methods and results By linkage analysis and exome sequencing, we identified deleterious mutations in SLC35A3 in these patients. SLC35A3 encodes the major Golgi uridine diphosphate _N_-acetylglucosamine (UDP-GlcNAc) transporter. In Golgi vesicles isolated from patient fibroblasts the transport of the respective nucleotide sugar was significantly reduced causing a massive decrease in the content of cell surface expressed highly branched _N_-glycans and a concomitant sharp increase of lower branched glycoforms.

Conclusions Spontaneous mutation in SLC35A3 has been discovered in cattle worldwide, recapitulating the human phenotype with arthrogryposis and additional skeletal defects known as Complex Vertebral Malformation syndrome. The skeletal anomalies in the mutant cattle and in our patients, and perhaps even the neurological symptoms are likely the consequence of the lack of high-branched _N_-glycans and the concomitant abundance of lower-branched glycoforms at the cell surface. This pattern has previously been associated with growth arrest and induction of differentiation. With this study, we add SLC35A3 to the gene list of autism spectrum disorders, and underscore the crucial importance of UDP-GlcNAc in the regulation of the _N_-glycan branching pathway in the Golgi apparatus.

Neurology

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