Molecular characterization of a large group of Mucopolysaccharidosis type IIIC patients reveals the evolutionary history of the disease
| Autor: | Bilge Noyan, Damian Labuda, Sandra Leistner-Segal, Roberto Giugliani, Alexey V. Pshezhetsky, Lúcia Lacerda, Jill Wood, Carla Martins, Mahdiyeh Behnam, Larbi Dridi, Nursel Elcioglu, Michael T. Geraghty, Paula Frassinetti Vasconcelos de Medeiros |
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| Rok vydání: | 2019 |
| Předmět: |
Male
Canada Protein Folding Azerbaijan Mucopolysaccharidosis Context (language use) Colombia Iran Biology Evolution Molecular Mucopolysaccharidosis III 03 medical and health sciences Acetyltransferases Chlorocebus aethiops Genetics medicine Lysosomal storage disease Animals Humans Missense mutation Genetics (clinical) Netherlands 030304 developmental biology Sanfilippo syndrome 0303 health sciences Mucopolysaccharidosis Type IIIC 030305 genetics & heredity Haplotype medicine.disease Founder Effect Pedigree Phylogeography Haplotypes Algeria COS Cells Mutation Female Poland Brazil Founder effect |
| Zdroj: | Human Mutation. 40:1084-1100 |
| ISSN: | 1059-7794 |
| DOI: | 10.1002/humu.23752 |
| Popis: | Mucopolysaccharidosis type IIIC (MPSIIIC) is a severe, rare autosomal recessive disorder caused by variants in the heparan-α-glucosaminide N-acetyltransferase (HGSNAT) gene which result in lysosomal accumulation of heparan sulfate. We analyzed clinical presentation, molecular defects and their haplotype context in 78 (27 novel) MPSIIIC cases from 22 countries, the largest group studied so far. We describe for the first time disease-causing variants in the patients from Brazil, Algeria, Azerbaijan, and Iran, and extend their spectrum within Canada, Colombia, Turkey, and the USA. Six variants are novel: two missense, c.773A>T/p.N258I and c.1267G>T/p.G423W, a nonsense c.164T>A/p.L55*, a splice-site mutation c.494-1G>A/p.[P165_L187delinsQSCYVTQAGVRWHHLGSLQALPPGFTPFSYLSLLSSWNC,P165fs], a deletion c.1348delG/p.(D450fs) and an insertion c.1479dupA/p.(Leu494fs). The missense HGSNAT variants lacked lysosomal targeting, enzymatic activity, and likely the correct folding. The haplotype analysis identified founder mutations, p.N258I, c.525dupT, and p.L55* in the Brazilian state of Paraiba, c.493+1G>A in Eastern Canada/Quebec, p.A489E in the USA, p.R384* in Poland, p.R344C and p.S518F in the Netherlands and suggested that variants c.525dupT, c.372-2G>A, and c.234+1G>A present in cis with c.564-98T>C and c.710C>A rare single-nucleotide polymorphisms, have been introduced by Portuguese settlers in Brazil. Altogether, our results provide insights into the origin, migration roots and founder effects of HGSNAT disease-causing variants, and reveal the evolutionary history of MPSIIIC. |
| Databáze: | OpenAIRE |
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