title: Intellectual disability and bleeding diathesis due to deficient CMP--sialic acid transport.
abstract: OBJECTIVE
  To identify the underlying genetic defect in a patient with intellectual disability, seizures, ataxia, macrothrombocytopenia, renal and cardiac involvement, and abnormal protein glycosylation.
  
  
  METHODS
  Genetic studies involved homozygosity mapping by 250K single nucleotide polymorphism array and SLC35A1 sequencing. Functional studies included biochemical assays for N-glycosylation and mucin-type O-glycosylation and SLC35A1-encoded cytidine 5'-monophosphosialic acid (CMP-sialic acid) transport after heterologous expression in yeast.
  
  
  RESULTS
  We performed biochemical analysis and found combined N- and O-glycosylation abnormalities and specific reduction in sialylation in this patient. Homozygosity mapping revealed homozygosity for the CMP-sialic acid transporter SLC35A1. Mutation analysis identified a homozygous c.303G > C (p.Gln101His) missense mutation that was heterozygous in both parents. Functional analysis of mutant SLC35A1 showed normal Golgi localization but 50% reduction in transport activity of CMP-sialic acid in vitro.
  
  
  CONCLUSIONS
  We confirm an autosomal recessive, generalized sialylation defect due to mutations in SLC35A1. The primary neurologic presentation consisting of ataxia, intellectual disability, and seizures, in combination with bleeding diathesis and proteinuria, is discriminative from a previous case described with deficient sialic acid transporter. Our study underlines the importance of sialylation for normal CNS development and regular organ function.
authors.affiliation: Department of Pediatrics, Medizinische Hochschule Hannover, Germany.
authors.forename: Miski
authors.initials: M
authors.lastname: Mohamed
authors.forename: Angel
authors.initials: A
authors.lastname: Ashikov
authors.forename: Mailys
authors.initials: M
authors.lastname: Guillard
authors.forename: Joris H
authors.initials: JH
authors.lastname: Robben
authors.forename: Samuel
authors.initials: S
authors.lastname: Schmidt
authors.forename: B
authors.initials: B
authors.lastname: van den Heuvel
authors.forename: Arjan P M
authors.initials: AP
authors.lastname: de Brouwer
authors.forename: Rita
authors.initials: R
authors.lastname: Gerardy-Schahn
authors.forename: Peter M T
authors.initials: PM
authors.lastname: Deen
authors.forename: Ron A
authors.initials: RA
authors.lastname: Wevers
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: Lefeber
authors.forename: Eva
authors.initials: E
authors.lastname: Morava
mesh_terms: D000293:Adolescent; D015153:Blotting, Western; D002648:Child; D003569:Cytidine Monophosphate N-Acetylneuraminic Acid / Q000378:metabolism*; D004252:DNA Mutational Analysis; D005260:Female; D006031:Glycosylation; D006474:Hemorrhagic Disorders / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D020125:Mutation, Missense; D033704:Nucleotide Transport Proteins / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: D033704:Nucleotide Transport Proteins; C491081:SLC35A1 protein, human; D003569:Cytidine Monophosphate N-Acetylneuraminic Acid