TY - JOUR
T1 - Intellectual disability and bleeding diathesis due to deficient CMP-sialic acid transport
AU - Mohamed, Miski
AU - Ashikov, Angel
AU - Guillard, Mailys
AU - Robben, Joris H.
AU - Schmidt, Samuel
AU - Van Den Heuvel, B.
AU - De Brouwer, Arjan P.M.
AU - Gerardy-Schahn, Rita
AU - Deen, Peter M.T.
AU - Wevers, Ron A.
AU - Lefeber, Dirk J.
AU - Morava, Eva
PY - 2013/8/13
Y1 - 2013/8/13
N2 - 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 59-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. Conclusion: 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.
AB - 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 59-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. Conclusion: 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.
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U2 - 10.1212/WNL.0b013e3182a08f53
DO - 10.1212/WNL.0b013e3182a08f53
M3 - Article
C2 - 23873973
AN - SCOPUS:84884496733
SN - 0028-3878
VL - 81
SP - 681
EP - 687
JO - Neurology
JF - Neurology
IS - 7
ER -