title: LAMA2 gene analysis in congenital muscular dystrophy: new mutations, prenatal diagnosis, and founder effect.
abstract: OBJECTIVE
  To determine if laminin-alpha2 deficiency is due to mutations in the LAMA2 gene or secondary to mutations in other congenital muscular dystrophy genes.
  
  
  METHODS
  We performed molecular analysis of LAMA2, by single-strand conformation polymorphism and sequencing, in 15 patients with undetectable or greatly reduced laminin-alpha2 expression. We also performed 4 prenatal diagnoses and investigated a founder effect.
  
  
  RESULTS
  We found 1 known and 9 previously undescribed LAMA2 mutations spanning all protein domains. These were nonsense or frameshifts causing laminin-alpha2 absence or, in 1 case, a homozygous missense mutation producing partial protein expression and milder phenotype. LAMA2 mutations were undetected in 5 patients, in 2 of whom FKRP mutations explained the phenotype. In 3 prenatal cases, the fetus was heterozygous for the mutation of interest and pregnancy continued; in 1 case, the fetus was affected and aborted. In 2 patients, the Cys967Stop mutation and identical haplotypes flanking the LAMA2 gene indicated a founder effect.
  
  
  CONCLUSIONS
  The clinical phenotype was severe in most patients with LAMA2 mutations and associated with undetectable protein expression. One case with no protein and another with partial expression had milder phenotypes. Typical white matter alterations on magnetic resonance imaging were found in all patients with LAMA2 mutations, supporting the utility of magnetic resonance imaging in differential diagnosis. The founder mutation (Cys967Stop) probably originated in Albania. Genetic characterization of affected families is mainly of use for prenatal diagnosis.
authors.affiliation: Divisions of Neuromuscular Diseases, Istituto Nazionale Neuorlogico C Besta, Bicocca Laboratories, Milano, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Di Blasi
authors.forename: Daniela
authors.initials: D
authors.lastname: Piga
authors.forename: Paolo
authors.initials: P
authors.lastname: Brioschi
authors.forename: Isabella
authors.initials: I
authors.lastname: Moroni
authors.forename: Antonella
authors.initials: A
authors.lastname: Pini
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ruggieri
authors.forename: Simona
authors.initials: S
authors.lastname: Zanotti
authors.forename: Graziella
authors.initials: G
authors.lastname: Uziel
authors.forename: Laura
authors.initials: L
authors.lastname: Jarre
authors.forename: Elvio
authors.initials: E
authors.lastname: Della Giustina
authors.forename: Carmela
authors.initials: C
authors.lastname: Scuderi
authors.forename: Christoffer
authors.initials: C
authors.lastname: Jonsrud
authors.forename: Renato
authors.initials: R
authors.lastname: Mantegazza
authors.forename: Lucia
authors.initials: L
authors.lastname: Morandi
authors.forename: Marina
authors.initials: M
authors.lastname: Mora
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D018703:Founder Effect; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D007797:Laminin / Q000172:deficiency / Q000235:genetics*; D008297:Male; D009136:Muscular Dystrophies / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D011247:Pregnancy; D011296:Prenatal Diagnosis
chemical_list: D007797:Laminin; C102645:laminin alpha 2