Congenital Disorder of Glycosylation Type Ia: Searching for the Origin of Common Mutations in PMM2

Abstract

SummaryCongenital Disorders of Glycosylation (CDG) are a group of recessive genetic disorders characterized by hypoglycosylation of glycoproteins. CDG-Ia, the most common type, is caused by mutations in the PMM2 gene, coding for a phosphomannomutase (PMM2; EC 5.4.2.8). The mutational spectrum of PMM2 comprises more than 80 different mutations but one of them, R141H, is particularly interesting due to its high frequency among CDG-Ia patients worldwide. In contrast, other mutations are ethnically or geographically restricted, such as D65Y which is only found in patients of Iberian ancestry.In the present study a population genetic approach was used in an attempt to clarify the origins of two important disease causing mutations: R141H and D65Y. Based on SNP and STR genotypic analysis, we ascertained an association between the R141H substitution and a particular haplotype, suggesting a common origin for all the mutated chromosomes. Similar results were found for D65Y, although the associated haplotype was different from that of R141H, suggesting independent origins for these two mutations. Our results enable us to infer an Iberian origin for the D65Y mutation.

The Molecular Landscape of Phosphomannose Mutase Deficiency in Iberian Peninsula: Identification of 15 Population-Specific Mutations

“…Of these 30 identified mutations, 13 have only been reported in our series of patients. The p.D65Y mutation was reported in a French study in a Portuguese patient, and a haplotypic association study confirmed its Iberian origin (Quelhas et al 2007), and the p.V44A mutation was reported in an Ecuatorian patient probably of Spanish ancestors, adding these two mutations to our population-specific group of mutations. It is to note that mutations p.N216I and p.T226S were also previously reported in patients of Mediterranean origin (France, Italy, and Greece) .…”

“…A large variety of mutations have been identified in our Iberian cohort of unrelated PMM2-CDG patients: 25 (83%) are missense mutations (Briones et al 2002;Quelhas et al 2007), four of them newly reported here (p.Y102C, p.T118S, p.P184T, and p.D209G); one nonsense (p.R123X) (Briones et al 2002), three affecting the splicing of mRNA (IVS3+ 2T>C; IVS3-1G>C and IVS7-9T>C) (Briones et al 2002;Vega et al 2009), and a deletion mediated by an Alu retrotransposition displaying the complete loss of exon 8 (Schollen et al 2007a). Of these 30 identified mutations, 13 have only been reported in our series of patients.…”

Genotypes and estimated prevalence of phosphomannomutase 2 deficiency in Turkey differ significantly from those in Europe

“…The carrier frequency of this variant ranges from 1 in 72 to 224 in Northern European populations (Schollen, Kjaergaard, Legius, Schwartz, & Matthijs, ; Vals et al, ), but is 1 in 1,311 in our sample. The high frequency of the p.Arg141His variant in Europe is attributed to heterozygote advantage against hepatitis viruses (Freeze & Westphal, ), but there is also evidence that it descends from a single origin before recombining into different haplotypes (Quelhas, Quental, Vilarinho, Amorim, & Azevedo, ). It is predominantly the high prevalence of this variant that contributes to the relatively high estimated prevalence of PMM2‐CDG (1:20,000) (Schollen et al, ), which is much higher than that calculated from our sample (1:286,726).…”

The Effects of PMM2-CDG-Causing Mutations on the Folding, Activity, and Stability of the PMM2 Protein

“…The clinical heterogeneity present in PMM2‐CDG patients, along with the practical absence of homozygosity among the studied patients, hinders a straightforward genotype–phenotype correlation for this disease. After the analysis of the reported genotypes carrying the studied mutations, we can conclude that just destabilizing mutations retaining residual activity have been detected in homozygosity, such as p.T237M and p.D65Y [Grunewald et al., ; Quelhas et al., ; Vega et al., ]. Furthermore, among the studied mutants, p.R162W and p.T237M have been associated with mild or moderate phenotypes [Grunewald et al., ; Quelhas et al., ), whereas p.V44A and p.D65Y have been related with more severe phenotypes [Grunewald et al., ; Quelhas et al., ; Schollen et al., ].…”