A case of pseudodominant inheritance of limb-girdle muscular dystrophy caused by mutations in the CAPN3 gene

Introduction. Limb-girdle muscular dystrophy (LGMD) includes more than 30 forms caused by mutations in genes located on autosomes. The most common form is calpain-3-related LGMD, with autosomal recessive inheritance pattern (OMIM 253600). An autosomal dominant form of LGMD (OMIM 618129) caused by c.643_663del heterozygous mutation in the CAPN3 gene is also supposed to exist. This article describes a family case of LGMD caused by mutations in the CAPN3 gene with pseudodominant inheritance. Materials and methods. Two patients with LGMD were studied: a 59-year-old woman and her 38-year-old daughter. Clinical, genealogical and molecular genetics methods were used: limb girdle muscular dystrophy MPS panel, Sanger sequencing of DNA of the proband, her affected daughter, and six first- and second-degree relatives across four generations. Results. It was found that identical variants of the nucleotide sequence, c.598_612del and c.1746-20CG, identified in the CAPN3 gene of the proband and her daughter, are in the trans position (compound heterozygous state), causing autosomal recessive calpain-3-related LGMD. This is an example of an incredibly rare pseudodominant inheritance of an autosomal recessive disease, established through indirect evidence that the probands husband is a heterozygous carrier of a nucleotide substitution in the CAPN3 gene. Conclusion. It is crucial to examine the marriage partner for heterozygous carrier status of a gene mutation responsible for the disease in family planning and when clarifying the childs prognosis for a patient with an autosomal recessive disease. Considering the existence of a late-onset (after 30 years) LGMD phenotype associated with the CAPN3 gene, differential diagnosis should begin with testing this gene in families with late disease onset.

Download Full-text

Allosteric Modulation of GSK-3β as a New Therapeutic Approach in Limb Girdle Muscular Dystrophy R1 Calpain 3-Related

International Journal of Molecular Sciences ◽

10.3390/ijms22147367 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7367

Author(s):

Anabel Rico ◽

Garazi Guembelzu ◽

Valle Palomo ◽

Ana Martínez ◽

Ana Aiastui ◽

...

Keyword(s):

Muscular Dystrophy ◽

Autosomal Recessive ◽

Glycogen Synthase ◽

Limb Girdle Muscular Dystrophy ◽

Pathophysiological Mechanism ◽

Calpain 3 ◽

Competitive Inhibitors ◽

Gsk 3Β ◽

Muscle Homeostasis ◽

Capn3 Gene

Limb-girdle muscular dystrophy R1 calpain 3-related (LGMDR1) is an autosomal recessive muscular dystrophy produced by mutations in the CAPN3 gene. It is a rare disease and there is no cure or treatment for the disease while the pathophysiological mechanism by which the absence of calpain 3 provokes the dystrophy in muscles is not clear. However, key proteins implicated in Wnt and mTOR signaling pathways, which regulate muscle homeostasis, showed a considerable reduction in their expression and in their phosphorylation in LGMDR1 patients’ muscles. Finally, the administration of tideglusib and VP0.7, ATP non-competitive inhibitors of glycogen synthase kinase 3β (GSK-3β), restore the expression and phosphorylation of these proteins in LGMDR1 cells, opening the possibility of their use as therapeutic options.

Download Full-text

Compound heterozygous c.598_612del and c.1746-20C > G CAPN3 genotype cause autosomal recessive limb-girdle muscular dystrophy-1: a case report

BMC Musculoskeletal Disorders ◽

10.1186/s12891-021-04920-3 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Evelina Siavrienė ◽

Gunda Petraitytė ◽

Birutė Burnytė ◽

Aušra Morkūnienė ◽

Violeta Mikštienė ◽

...

Keyword(s):

Muscular Dystrophy ◽

Autosomal Recessive ◽

Premature Termination Codon ◽

Limb Girdle Muscular Dystrophy ◽

Lower Limbs ◽

Compound Heterozygous ◽

Targeted Next Generation Sequencing ◽

Splicing Variant ◽

Cdna Analysis ◽

Compound Heterozygous Variants

Abstract Background Autosomal recessive limb–girdle muscular dystrophy-1 (LGMDR1), also known as calpainopathy, is a genetically heterogeneous disorder characterised by progression of muscle weakness. Homozygous or compound heterozygous variants in the CAPN3 gene are known genetic causes of this condition. The aim of this study was to confirm the molecular consequences of the CAPN3 variant NG_008660.1(NM_000070.3):c.1746-20C > G of an individual with suspected LGMDR1 by extensive complementary DNA (cDNA) analysis. Case presentation In the present study, we report on a male with proximal muscular weakness in his lower limbs. Compound heterozygous NM_000070.3:c.598_612del and NG_008660.1(NM_000070.3):c.1746-20C > G genotype was detected on the CAPN3 gene by targeted next-generation sequencing (NGS). To confirm the pathogenicity of the variant c.1746-20C > G, we conducted genetic analysis based on Sanger sequencing of the proband’s cDNA sample. The results revealed that this splicing variant disrupts the original 3′ splice site on intron 13, thus leading to the skipping of the DNA fragment involving exon 14 and possibly exon 15. However, the lack of exon 15 in the CAPN3 isoforms present in a blood sample was explained by cell-specific alternative splicing rather than an aberrant splicing mechanism. In silico the c.1746-20C > G splicing variant consequently resulted in frameshift and formation of a premature termination codon (NP_000061.1:p.(Glu582Aspfs*62)). Conclusions Based on the results of our study and the literature we reviewed, both c.598_612del and c.1746-20C > G variants are pathogenic and together cause LGMDR1. Therefore, extensive mRNA and/or cDNA analysis of splicing variants is critical to understand the pathogenesis of the disease.

Download Full-text

Limb-girdle muscular dystrophy type 2A in Brazilian children

Arquivos de Neuro-Psiquiatria ◽

10.1590/0004-282x20150168 ◽

2015 ◽

Vol 73 (12) ◽

pp. 993-997 ◽

Cited By ~ 5

Author(s):

Marco Antônio Veloso de Albuquerque ◽

Osório Abath Neto ◽

Francisco Marcos Alencar da Silva ◽

Edmar Zanoteli ◽

Umbertina Conti Reed

Keyword(s):

Muscular Dystrophy ◽

Disease Onset ◽

Limb Girdle Muscular Dystrophy ◽

Lower Limbs ◽

Clinical Aspects ◽

Mri Findings ◽

Muscle Mri ◽

Scapular Winging ◽

Muscle Biopsies ◽

Capn3 Gene

ABSTRACT Calpainopathy is an autosomal recessive limb girdle muscular dystrophy (LGMD2A) caused by mutations in CAPN3 gene. Objective To present clinical and histological findings in six children with a molecular diagnosis of LGMD2A and additionally the MRI findings in two of them. Method We retrospectively assessed medical records of 6 patients with mutation on CAPN3 gene. Results All patients were female (three to 12 years). The mean of age of disease onset was 9 years. All of them showed progressive weakness with predominance in lower limbs. Other findings were scapular winging, joint contractures and calf hypertrophy. One female had a more severe phenotype than her dizygotic twin sister that was confirmed by muscle MRI. Muscle biopsies showed a dystrophic pattern in all patients. Conclusion In this cohort of children with LGMD2A, the clinical aspects were similar to adults with the same disorder.

Download Full-text

Calcium Mechanisms in Limb-Girdle Muscular Dystrophy with CAPN3 Mutations

International Journal of Molecular Sciences ◽

10.3390/ijms20184548 ◽

2019 ◽

Vol 20 (18) ◽

pp. 4548 ◽

Cited By ~ 2

Author(s):

Jaione Lasa-Elgarresta ◽

Laura Mosqueira-Martín ◽

Neia Naldaiz-Gastesi ◽

Amets Sáenz ◽

Adolfo López de Munain ◽

...

Keyword(s):

Muscular Dystrophy ◽

Inclusion Body Myositis ◽

Disease Onset ◽

Therapeutic Strategies ◽

Limb Girdle Muscular Dystrophy ◽

Sporadic Inclusion Body Myositis ◽

Children And Young Adults ◽

Novel Approaches ◽

Progressive Weakness ◽

Capn3 Gene

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 Ca2+ 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 Ca2+ homeostasis, such as LGMD2B/LGMDR2 or sporadic inclusion body myositis.

Download Full-text

A case report: autosomal recessive limb girdle muscular dystrophy caused by a novel mutation (c. 287A > G) in POMT2 gene of a Chinese Han patient

10.21203/rs.2.483/v1 ◽

2019 ◽

Author(s):

Yanlu Gao ◽

Zhixia Kang ◽

Xiaojing Wei ◽

Jing Miao ◽

Xuefan Yu

Keyword(s):

Creatine Kinase ◽

Cognitive Impairment ◽

Case Report ◽

Muscular Dystrophy ◽

Muscle Weakness ◽

Autosomal Recessive ◽

Limb Girdle Muscular Dystrophy ◽

Compound Heterozygous ◽

Proximal Muscle Weakness ◽

Proximal Muscle

Abstract BACKGROUND Autosomal recessive limb girdle muscular dystrophy 2N is caused by mutations in the POMT2 gene. The disease is characterized by proximal muscle weakness,with minimal progression, with cognitive impairment,a significantly elevated serum level of creatine kinase. CASE PRESENTATION A 9-year-old boy presented with proximal muscle weakness since the last 4 years,with minimal progression.There was no significant family history.Medical examination showed no generalized muscle hypertrophy. Serum creatine kinase level was 52-fold higher than the normal value. Wechsler Intelligence scale for Children (WISC, 4) suggested mild cognitive impairment (IQ =74). DNA sequence analysis identified a novel missense mutation (c. 287A > G) and a known mutation (c. 1261C > T). CONCLUSIONS This case report of autosomal recessive limb girdle muscular dystrophy 2N caused by a novel compound heterozygous mutation expands the genotypic spectrum of POMT2 gene.

Download Full-text

Аutosomal recessive limb-girdle muscular dystrophy type 2A: two cases in Ukraine with different age of onset

Medicni perspektivi (Medical perspectives) ◽

10.26641/2307-0404.2021.3.242343 ◽

2021 ◽

Vol 26 (3) ◽

pp. 212-218

Author(s):

Yu.H. Antipkin ◽

L.H. Kyrylova ◽

O.O. Miroshnykov ◽

O.O. Yuzva ◽

V.V. Orzheshkovskyi ◽

...

Keyword(s):

Muscular Dystrophy ◽

Muscle Weakness ◽

Blood Test ◽

Autosomal Recessive ◽

Age Of Onset ◽

Adductor Muscle ◽

Limb Girdle Muscular Dystrophy ◽

Semitendinosus Muscle ◽

Adductor Muscles ◽

Capn3 Gene

The paper reports on two cases of young women from Ukraine with autosomal recessive limb-girdle muscular dystrophy type 2A with different age of symptoms onset and an absence of any family history presented with gradual onset of proximal muscle weakness in four limbs and thinning of shoulders, arms and thighs. Both patients had elevated creatine phosphokinase level and c.550delA mutations in CAPN3 gene. Sequence analysis and deletion/duplication testing of the 159 genes from skeletal muscles disease testing panel of 5-year-old girl identified deletion of exon 8 (heterozygous) and c.550delA (p.Thr184Argfs*36) mutation (heterozygous), were in CAPN3 gene. Magnetic Resonance Imaging of soft tissue of the proximal lower extremities was performed which showed signs of symmetrical atrophic changes in the major adductor muscle, the long and short adductor muscles, the semitendinosus muscle of the thigh, as a manifestations of autosomal recessive limb-girdle muscular dystrophy type 2A. Homozygous, pathogenic variant of the defect in the CAPN3 gene c.550del (p.Thr184Argfs * 36) was identified in a 25-year-old woman. Type 2A is the most common form of limb-girdle muscular dystrophy, accounting for about 30% of cases. The autosomal recessive limb-girdle muscular dystrophy type 2A is on caused by mutations in the CAPN3 gene, and it is characterized by selective atrophy and weakness of proximal limb and girdle muscles. The age of onset of muscle weakness is extremely variable; the most common being between 8 and 15 years, although it can range between 2 and 50 years. The diagnosis can be suspected by findings on a muscle biopsy or when a doctor experienced in muscular dystrophy examines you. A serum creatine kinase blood test may also show raised levels which indicate a problem in the muscles. The diagnosis has to be confirmed by means of identifying a mutation in the CAPN3 gene which is done on a deoxyribonucleic acid sample from a blood test. To date there are no specific treatments for limb-girdle muscular dystrophy, however careful management of the symptoms of the condition can improve a person’s quality of life. Joint contractures (tightening) can occur in limb-girdle muscular dystrophy and therefore regular physiotherapy is recommended.

Download Full-text