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Molecular heterogeneity of myophosphorylase deficiency (Mcardle's disease): A genotype‐phenotype correlation study
Author(s) -
Martín Miguel A.,
Rubio Juan C.,
Buchbinder Jenny,
FernándezHojas Roberto,
Del Hoyo Pilar,
Teijeira Susana,
Gámez Josep,
Navarro Carmen,
Fernández José M.,
Cabello Ana,
Campos Yolanda,
Cervera Carlos,
Culebras José M.,
Andreu Antoni L.,
Fletterick Robert,
Arenas Joaquín
Publication year - 2001
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.1225
Subject(s) - phenotype , genotype , disease , correlation , genetic heterogeneity , genotype phenotype distinction , biology , genetics , medicine , gene , geometry , mathematics
We report on 54 Spanish patients with McArdle's disease from 40 unrelated families. Molecular analysis revealed that the most common R49X mutation was present in 70% of patients and 55% of alleles. The G204S mutation was less frequent and found in 14.8% of patients and 9% of mutant alleles. The W797R mutation was observed in 16.5% of patients, accounting for 13.7% of mutant alleles. Moreover, 78% of mutant alleles among Spanish patients can be identified by using polymerase chain reaction‐restriction fragment length polymorphism analysis for the R49X, G204S, and W797R mutations, which makes noninvasive diagnosis possible through molecular genetic analysis of blood DNA. Six novel mutations were found. Three were missense mutations, E348K, R601W, and A703V; two nonsense mutations, E124X and Q754X; and one single base pair deletion, 533 delA. No clear genotype‐phenotype correlation emerges from our study. Most of the mutations of uncharged and solvent inaccessible residues and the truncations must disrupt the basic structure of the protein. The mutations of charged residues would be expected to interfere with internal hydrogen bonding networks, introducing severe incompatible partnering that is caused by poor packing or electrostatic repulsions.