LAMA2 gene analysis in congenital muscular dystrophy: new mutations, prenatal diagnosis, and founder effect.
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.
Di Blasi
Claudia
C
Divisions of Neuromuscular Diseases, Istituto Nazionale Neuorlogico C Besta, Bicocca Laboratories, Milano, Italy.
Piga
Daniela
D
Brioschi
Paolo
P
Moroni
Isabella
I
Pini
Antonella
A
Ruggieri
Alessandra
A
Zanotti
Simona
S
Uziel
Graziella
G
Jarre
Laura
L
Della Giustina
Elvio
E
Scuderi
Carmela
C
Jonsrud
Christoffer
C
Mantegazza
Renato
R
Morandi
Lucia
L
Mora
Marina
M
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
D007797:Laminin; C102645:laminin alpha 2