title: Origin and spread of a common deletion causing mucolipidosis type II: insights from patterns of haplotypic diversity.
abstract: Mucolipidosis II (ML II alpha/beta), or I-cell disease, is a rare genetic disease in which activity of the uridine diphosphate (UDP)-N-acetylglucosamine:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase (GlcNAc-phosphotransferase) is absent. GlcNAc-phosphotransferase is a multimeric enzyme encoded by two genes, GNPTAB and GNPTG. A spectrum of mutations in GNPTAB has been recently reported to cause ML II alpha/beta. Most of these mutations were found to be private or rare. However, the mutation c.3503_3504delTC has been detected among Israeli and Palestinian Arab-Muslim, Turkish, Canadian, Italian, Portuguese, Irish traveller and US patients. We analysed 44 patients who were either homozygous or compound heterozygous for this deletion (22 Italians, 8 Arab-Muslims, 1 Turk, 3 Argentineans, 3 Brazilians, 2 Irish travellers and 5 Portuguese) and 16 carriers (15 Canadians and 1 Italian) for three intragenic polymorphisms: c.-41_-39delGGC, c.18G>A and c.1932A>G as well as two microsatellite markers flanking the GNPTAB gene (D12S1607 and D12S1727). We identified a common haplotype in all chromosomes bearing the c.3503_3504delTC mutation. In summary, we showed that patients carrying the c.3503_3504delTC deletion presented with a common haplotype, which implies a common origin of this mutation. Additionally, the level of diversity observed at the most distant locus indicates that the mutation is relatively ancient (around 2063 years old), and the geographical distribution further suggests that it probably arose in a peri-Mediterranean region.
authors.affiliation: Medical Genetics Center Jacinto Magalhães, Research and Development Unit, Department of Genetics, INSA, Portugal.
authors.forename: M F
authors.initials: MF
authors.lastname: Coutinho
authors.forename: M
authors.initials: M
authors.lastname: Encarnação
authors.forename: R
authors.initials: R
authors.lastname: Gomes
authors.forename: L
authors.initials: L
authors.lastname: da Silva Santos
authors.forename: S
authors.initials: S
authors.lastname: Martins
authors.forename: D
authors.initials: D
authors.lastname: Sirois-Gagnon
authors.forename: R
authors.initials: R
authors.lastname: Bargal
authors.forename: M
authors.initials: M
authors.lastname: Filocamo
authors.forename: A
authors.initials: A
authors.lastname: Raas-Rothschild
authors.forename: B
authors.initials: B
authors.lastname: Tappino
authors.forename: C
authors.initials: C
authors.lastname: Laprise
authors.forename: G K
authors.initials: GK
authors.lastname: Cury
authors.forename: I V
authors.initials: IV
authors.lastname: Schwartz
authors.forename: O
authors.initials: O
authors.lastname: Artigalás
authors.forename: M J
authors.initials: MJ
authors.lastname: Prata
authors.forename: S
authors.initials: S
authors.lastname: Alves
mesh_terms: D018912:Arabs / Q000235:genetics* / Q000266:history; D002170:Canada; D004252:DNA Mutational Analysis; D003710:Demography / Q000266:history; D005060:Europe; D005260:Female; D005787:Gene Frequency; D006239:Haplotypes; D006579:Heterozygote; D049690:History, Ancient; D006720:Homozygote; D006801:Humans; D007843:Latin America; D008297:Male; D019083:Mediterranean Region; D009081:Mucolipidoses / Q000235:genetics* / Q000503:physiopathology; D010802:Phylogeny; D011110:Polymorphism, Genetic; D017384:Sequence Deletion; D017855:Transferases (Other Substituted Phosphate Groups) / Q000172:deficiency / Q000235:genetics; D014421:Turkey
chemical_list: D017855:Transferases (Other Substituted Phosphate Groups); C030012:UDP-N-acetylglucosamine-lysosomal-enzyme-N-acetylglucosaminephosphotransferase