Article Text

Download PDFPDF
Extensive scanning of the calpain-3 gene broadens the spectrum of LGMD2A phenotypes
  1. G Piluso1,*,
  2. L Politano2,*,
  3. S Aurino3,
  4. M Fanin4,
  5. E Ricci6,
  6. V M Ventriglia1,*,
  7. A Belsito3,
  8. A Totaro3,
  9. V Saccone3,
  10. H Topaloglu7,
  11. A C Nascimbeni5,
  12. L Fulizio5,
  13. A Broccolini6,
  14. N Canki-Klain8,
  15. L I Comi2,
  16. G Nigro2,
  17. C Angelini4,
  18. V Nigro1
  1. 1Dipartimento di Patologia Generale e Centro di Eccellenza per le malattie cardiovascolari, Seconda Università di Napoli, Naples, Italy
  2. 2Servizio di Cardiomiologia e Genetica Medica, Dipartimento di Medicina Sperimentale, Seconda Università di Napoli
  3. 3Telethon Institute of Genetics and Medicine (TIGEM), Naples
  4. 4Dipartimento di Neuroscienze, Università di Padova, Padova, Italy
  5. 5Venetian Institute of Molecular Medicine, Padova
  6. 6Dipartimento di Neuroscienze, Università Cattolica, Rome, Italy
  7. 7Department of Child Neurology, Hacettepe Children’s Hospital, Ankara University, Ankara, Turkey
  8. 8Croatian Institute for Brain Research, Zagreb University Medical School, Zagreb, Croatia
  1. Correspondence to:
 Professor Vincenzo Nigro
 Dipartimento di Patologia Generale, Facoltà di Medicina e Chirurgia, Seconda Università degli Studi di Napoli, Via Luigi De Crecchio 7, 80138 Naples, Italy;


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.

Patients: 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.

  • CK, creatine kinase
  • HT-DHPLC, high throughput denaturing high performance liquid chromatography
  • LGMD, limb girdle muscular dystrophy
  • limb girdle muscular dystrophy
  • calpain 3
  • DNA pooling

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.


  • * Both authors contributed equally to this work

  • Competing interests: none declared