Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:3.4.22.54 (
calpain 3
)
430
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Limb-girdle muscular dystrophy recessive 1 (LGMDR1), previously known as LGMD2A, is a
rare disease
caused by mutations in the
CAPN3
gene. It is characterized by progressive weakness of shoulder, pelvic, and proximal limb muscles that usually appears in children and young adults and results in loss of ambulation within 20 years after disease onset in most patients. The pathophysiological mechanisms involved in LGMDR1 remain mostly unknown, and to date, there is no effective treatment for this disease. Here, we review clinical and experimental evidence suggesting that dysregulation of Ca
2+
homeostasis in the skeletal muscle is a significant underlying event in this muscular dystrophy. We also review and discuss specific clinical features of LGMDR1,
CAPN3
functions, novel putative targets for therapeutic strategies, and current approaches aiming to treat LGMDR1. These novel approaches may be clinically relevant not only for LGMDR1 but also for other muscular dystrophies with secondary calpainopathy or with abnormal Ca
2+
homeostasis, such as LGMD2B/LGMDR2 or sporadic inclusion body myositis.
...
PMID:Calcium Mechanisms in Limb-Girdle Muscular Dystrophy with
CAPN3
Mutations. 3154 Mar 2
Objective:
Inherited myopathies comprise more than 200 different individually
rare disease
-subtypes, but when combined together they have a high prevalence of 1 in 6,000 individuals across the world. Our goal was to determine for the first time the clinical- and gene-variant spectrum of genetic myopathies in a substantial cohort study of the Indian subcontinent.
Methods:
In this cohort study, we performed the first large clinical exome sequencing (ES) study with phenotype correlation on 207 clinically well-characterized inherited myopathy-suspected patients from the Indian subcontinent with diverse ethnicities.
Results:
Clinical-correlation driven definitive molecular diagnosis was established in 49% (101 cases; 95% CI, 42-56%) of patients with the major contributing pathogenicity in either of three genes,
GNE
(28%; GNE-myopathy),
DYSF
(25%; Dysferlinopathy), and
CAPN3
(19%; Calpainopathy). We identified 65 variant alleles comprising 37 unique variants in these three major genes. Seventy-eight percent of the
DYSF
patients were homozygous for the detected pathogenic variant, suggesting the need for carrier-testing for autosomal-recessive disorders like Dysferlinopathy that are common in India. We describe the observed clinical spectrum of myopathies including uncommon and rare subtypes in India: Sarcoglycanopathies (
SGCA/B/D/G
), Collagenopathy (
COL6A1/2/3
), Anoctaminopathy (
ANO5
), telethoninopathy (
TCAP
), Pompe-disease (
GAA
), Myoadenylate-deaminase-deficiency-myopathy (
AMPD1
), myotilinopathy (
MYOT
), laminopathy (
LMNA
), HSP40-proteinopathy (
DNAJB6
), Emery-Dreifuss-muscular-dystrophy (
EMD
), Filaminopathy (
FLNC
), TRIM32-proteinopathy (
TRIM32
), POMT1-proteinopathy (
POMT1
), and Merosin-deficiency-congenital-muscular-dystrophy-type-1 (
LAMA2
). Thirteen patients harbored pathogenic variants in >1 gene and had unusual clinical features suggesting a possible role of synergistic-heterozygosity/digenic-contribution to disease presentation and progression.
Conclusions:
Application of clinically correlated ES to myopathy diagnosis has improved our understanding of the clinical and genetic spectrum of different subtypes and their overlaps in Indian patients. This, in turn, will enhance the global gene-variant-disease databases by including data from developing countries/continents for more efficient clinically driven molecular diagnostics.
...
PMID:Clinical and Genomic Evaluation of 207 Genetic Myopathies in the Indian Subcontinent. 3325 Aug 42
