Extensive scanning of the calpain-3 gene broadens the spectrum of LGMD2A phenotypes.
BACKGROUND
The limb girdle muscular dystrophies (LGMD) are a heterogeneous group of Mendelian disorders highlighted by weakness of the pelvic and shoulder girdle muscles. Seventeen autosomal loci have been so far identified and genetic tests are mandatory to distinguish among the forms. Mutations at the calpain 3 locus (CAPN3) cause LGMD type 2A.


OBJECTIVE
To obtain unbiased information on the consequences of CAPN3 mutations.


METHODS
530 subjects with different grades of symptoms and 300 controls.


METHODS
High throughput denaturing HPLC analysis of DNA pools.


RESULTS
141 LGMD2A cases were identified, carrying 82 different CAPN3 mutations (45 novel), along with 18 novel polymorphisms/variants. Females had a more favourable course than males. In 94% of the more severely affected patient group, the defect was also discovered in the second allele. This proves the sensitivity of the approach. CAPN3 mutations were found in 35.1% of classical LGMD phenotypes. Mutations were also found in 18.4% of atypical patients and in 12.6% of subjects with high serum creatine kinase levels.


CONCLUSIONS
A non-invasive and cost-effective strategy, based on the high throughput denaturing HPLC analysis of DNA pools, was used to obtain unbiased information on the consequences of CAPN3 mutations in the largest genetic study ever undertaken. This broadens the spectrum of LGMD2A phenotypes and sets the carrier frequency at 1:103.
Piluso
G
G
Dipartimento di Patologia Generale e Centro di Eccellenza per le malattie cardiovascolari, Seconda Università di Napoli, Naples, Italy.
Politano
L
L
Aurino
S
S
Fanin
M
M
Ricci
E
E
Ventriglia
V M
VM
Belsito
A
A
Totaro
A
A
Saccone
V
V
Topaloglu
H
H
Nascimbeni
A C
AC
Fulizio
L
L
Broccolini
A
A
Canki-Klain
N
N
Comi
L I
LI
Nigro
G
G
Angelini
C
C
Nigro
V
V
D000328:Adult; D002154:Calpain / Q000235:genetics*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D015331:Cohort Studies; D004247:DNA / Q000097:blood / Q000378:metabolism; D005260:Female; D005808:Genes, Recessive; D005820:Genetic Testing / Q000379:methods*; D006801:Humans; D008297:Male; D009124:Muscle Proteins / Q000235:genetics*; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D011110:Polymorphism, Genetic
D009124:Muscle Proteins; D004247:DNA; C105884:CAPN3 protein, human; D002154:Calpain