title: Asymptomatic carriers for homozygous novel mutations in the FKRP gene: the other end of the spectrum.
abstract: Autosomal recessive limb-girdle muscular dystrophy linked to 19q13.3 (LGMD2I) was recently related to mutations in the fukutin-related protein gene (FKRP) gene. Pathogenic changes in the same gene were detected in congenital muscular dystrophy patients (MDC1C), a severe disorder. We have screened 86 LGMD genealogies to assess the frequency and distribution of mutations in the FKRP gene in Brazilian LGMD patients. We found 13 Brazilian genealogies, including 20 individuals with mutations in the FKRP gene, and identified nine novel pathogenic changes. The commonest C826A European mutation was found in 30% (9/26) of the mutated LGMD2I alleles. One affected patient homozygous for the FKRP (C826A) mutation also carries a missense R125H change in one allele of the caveolin-3 gene (responsible for LGMD1C muscular dystrophy). Two of her normal sibs were found to be double heterozygotes. In two unrelated LGMD2I families, homozygous for novel missense mutations, we identified four asymptomatic carriers, all older than 20 years. Genotype-phenotype correlation studies in the present study as well as in patients from different populations suggests that the spectrum of variability associated with mutations in the FKRP gene seems to be wider than in other forms of LGMD. It also reinforces the observations that pathogenic mutations are not always determinant of an abnormal phenotype, suggesting the possibility of other mechanisms modulating the severity of the phenotype that opens new avenues for therapeutic approaches.
authors.affiliation: 1Centro de Estudos do Genoma Humano, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Flavia
authors.initials: F
authors.lastname: de Paula
authors.forename: Natássia
authors.initials: N
authors.lastname: Vieira
authors.forename: Alessandra
authors.initials: A
authors.lastname: Starling
authors.forename: Lydia Uraco
authors.initials: LU
authors.lastname: Yamamoto
authors.forename: Bruno
authors.initials: B
authors.lastname: Lima
authors.forename: Rita
authors.initials: R
authors.lastname: de Cássia Pavanello
authors.forename: Mariz
authors.initials: M
authors.lastname: Vainzof
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Nigro
authors.forename: Mayana
authors.initials: M
authors.lastname: Zatz
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D002888:Chromosomes, Human, Pair 19; D017931:DNA Primers; D005260:Female; D006580:Genetic Carrier Screening; D006720:Homozygote; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D010430:Pentosyltransferases; D011506:Proteins / Q000235:genetics*
chemical_list: D017931:DNA Primers; D011506:Proteins; C443107:FKRP protein, human; D010430:Pentosyltransferases