title: NDST1 missense mutations in autosomal recessive intellectual disability.
abstract: NDST1 was recently proposed as a candidate gene for autosomal recessive intellectual disability in two families. It encodes a bifunctional GlcNAc N-deacetylase/N-sulfotransferase with important functions in heparan sulfate biosynthesis. In mice, Ndst1 is crucial for embryonic development and homozygous null mutations are perinatally lethal. We now report on two additional unrelated families with homozygous missense NDST1 mutations. All mutations described to date predict the substitution of conserved amino acids in the sulfotransferase domain, and mutation modeling predicts drastic alterations in the local protein conformation. Comparing the four families, we noticed significant overlap in the clinical features, including both demonstrated and apparent intellectual disability, muscular hypotonia, epilepsy, and postnatal growth deficiency. Furthermore, in Drosophila, knockdown of sulfateless, the NDST ortholog, impairs long-term memory, highlighting its function in cognition. Our data confirm NDST1 mutations as a cause of autosomal recessive intellectual disability with a distinctive phenotype, and support an important function of NDST1 in human development.
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Miriam S
authors.initials: MS
authors.lastname: Reuter
authors.forename: Luciana
authors.initials: L
authors.lastname: Musante
authors.forename: Hao
authors.initials: H
authors.lastname: Hu
authors.forename: Stefan
authors.initials: S
authors.lastname: Diederich
authors.forename: Heinrich
authors.initials: H
authors.lastname: Sticht
authors.forename: Arif B
authors.initials: AB
authors.lastname: Ekici
authors.forename: Steffen
authors.initials: S
authors.lastname: Uebe
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Wienker
authors.forename: Oliver
authors.initials: O
authors.lastname: Bartsch
authors.forename: Ulrich
authors.initials: U
authors.lastname: Zechner
authors.forename: Cornelia
authors.initials: C
authors.lastname: Oppitz
authors.forename: Krystyna
authors.initials: K
authors.lastname: Keleman
authors.forename: Rami Abou
authors.initials: RA
authors.lastname: Jamra
authors.forename: Hossein
authors.initials: H
authors.lastname: Najmabadi
authors.forename: Susann
authors.initials: S
authors.lastname: Schweiger
authors.forename: André
authors.initials: A
authors.lastname: Reis
authors.forename: Kimia
authors.initials: K
authors.lastname: Kahrizi
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D030801:Animals, Genetically Modified; D001522:Behavior, Animal; D002648:Child; D002675:Child, Preschool; D019295:Computational Biology; D003241:Consanguinity; D004252:DNA Mutational Analysis; D004330:Drosophila / Q000235:genetics; D019066:Facies; D005260:Female; D055785:Gene Knockdown Techniques; D005808:Genes, Recessive; D055106:Genome-Wide Association Study; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008958:Models, Molecular; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011487:Protein Conformation; D015238:Sulfotransferases / Q000737:chemistry / Q000235:genetics*; D055815:Young Adult
chemical_list: D015238:Sulfotransferases; C021350:heparitin sulfotransferase
keywords: NDST1; autosomal recessive intellectual disability; heparan sulfate biosynthesis; sulfateless