scholarly journals Recessive myotonia congenita caused by a homozygous splice site variant in CLCN1 gene: a case report

2020 ◽  
Vol 21 (S1) ◽  
Author(s):  
Peter Sparber ◽  
Margarita Sharova ◽  
Alexandra Filatova ◽  
Olga Shchagina ◽  
Evgeniya Ivanova ◽  
...  
Keyword(s):  
Functional Analysis ◽  
Splice Site ◽  
Muscle Relaxation ◽  
Neuromuscular Disorders ◽  
Voluntary Contraction ◽  
Muscle Stiffness ◽  
Loss Of Function ◽  
Myotonia Congenita ◽  
Clcn1 Gene ◽  
Splice Site Variant

Abstract Background Myotonia congenita is a rare neuromuscular disease, which is characterized by a delay in muscle relaxation after evoked or voluntary contraction. Myotonia congenita can be inherited in a dominant (Thomsen disease) and recessive form (Becker disease) and both are caused by pathogenic variants in the CLCN1 gene. Noncanonical splice site variants are often classified as variants of uncertain significance, due to insufficient accuracy of splice-predicting tools. Functional analysis using minigene plasmids is widely used in such cases. Moreover, functional analysis is very useful in investigation of the disease pathogenesis, which is necessary for development of future therapeutic approaches. To our knowledge only one noncanonical splice site variant in the CLCN1 gene was functionally characterized to date. We further contribute to this field by evaluation the molecular mechanism of splicing alteration caused by the c.1582 + 5G > A in a homozygous state. Case presentation We report a clinical case of an affected 6-y.o boy with athletic appearance due to muscle hypertrophy, calf muscle stiffness, cramping and various myotonic signs in a consanguineous family with no history of neuromuscular disorders. The neurological examination showed percussion-activated myotonia in the hands and legs. Plasma creatine kinase enzyme and transaminases levels were normal. Electromyography at the time of examination shows myotonic runs in the upper and lower extremities. Conclusions Functional analysis of the variant in a minigene system showed alteration of splicing leading to loss of function, thereby confirming that the variant is pathogenic.

scholarly journals Myotonia Congenita: Clinical Characteristic and Mutation Spectrum of CLCN1 in Chinese Patients

2021 ◽  
Vol 9 ◽  
Author(s):  
Chaoping Hu ◽  
Yiyun Shi ◽  
Lei Zhao ◽  
Shuizhen Zhou ◽  
Xihua Li
Keyword(s):  
Literature Review ◽  
Muscle Relaxation ◽  
Laboratory Data ◽  
Genetic Diagnosis ◽  
Muscle Stiffness ◽  
Chinese Patients ◽  
Myotonia Congenita ◽  
Warm Up ◽  
Chinese Populations ◽  
Whole Exome

Background:CLCN1-related myotonia congenita (MC) is one of the most common forms of non-dystrophic myotonia, in which muscle relaxation is delayed after voluntary or evoked contraction. However, there is limited data of clinical and molecular spectrum of MC patients in China.Patients and Methods: Five patients with myotonia congenita due to mutations in CLCN1 gene were enrolled, which were identified through trio-whole-exome sequencing or panel-based next-generation sequencing test. The clinical presentation, laboratory data, electrophysiological tests, muscular pathology feature, and genetic results were collected and reviewed. We also searched all previously reported cases of MC patients with genetic diagnosis in Chinese populations, and their data were reviewed.Results: The median onset age of five patients was 3.0 years old, ranging from 1.0 to 5.0 years old, while the median age of admit was 5.0 years old, ranging from 3.5 to 8.8 years old. Five patients complained of muscle stiffness when rising from chairs or starting to climb stairs (5/5, 100.0%), four patients complained of delayed relaxation of their hands after forceful grip (4/5, 80.0%), all of which improved with exercise (warm-up phenomenon) (5/5, 100%). Electromyogram was conducted in five patients, which all revealed myotonic change (100%). Genetic tests revealed nine potential disease-causing variants in CLCN1 gene, including two novel variants: c.962T>A (p.V321E) and c.1250A>T (p.E417V). Literature review showed that 43 MC Chinese patients with genetic diagnosis have been reported till now (including our five patients). Forty-seven variants in CLCN1 gene were found, which consisted of 33 missense variants, 6 nonsense variants, 5 frame-shift variants, and 3 splicing variants. Variants in exon 8, 15, 12, and 16 were most prevalent, while the most common variants were c.892G>A (p.A298T) (n = 9), c.139C>T (p.R47W) (n = 3), c.1205C>T(p.A402V) (n = 3), c.1657A>T (p.I553F) (n = 3), c.1679T>C (p.M560T) (n = 3), c.350A>G (p.D117G) (n = 2), c.762C>G (p.C254W) (n = 2), c.782A>G (P.Y261C) (n = 2), and c.1277C>A (p.T426N) (n = 2).Conclusion: Our results reported five CLCN1-related MC patients, which expanded the clinical and genetic spectrum of MC patients in China. Based on literature review, 43MC Chinese patients with genetic diagnosis have been reported till now, and variants in exon eight were most prevalent in Chinese MC patients while c.892G>A (p.A298T) was probably a founder mutation.

scholarly journals Spinal and bulbar muscular atrophy with pseudomyotonia phenomena: a clinical case report

2020 ◽  
Vol 9 (4) ◽  
pp. 51-56
Author(s):  
S. S. Nikitin ◽  
V. N. Grigoryeva ◽  
K. A. Mashkovich ◽  
O. L. Mironovich ◽  
N. V. Ryadninskaya ◽  
...  
Keyword(s):  
Skeletal Muscles ◽  
Clinical Case ◽  
Muscular Atrophy ◽  
Muscle Relaxation ◽  
Serum Testosterone ◽  
Voluntary Contraction ◽  
Muscle Stiffness ◽  
Gene Coding ◽  
Trinucleotide Expansion ◽  
Clinical Description

A clinical description of a 28-year-old man with spinal and bulbar muscular atrophy diagnosed on the basis of the CAG-trinucleotide expansion in the gene coding androgen receptor is presented. He exhibited skeletal muscles and tongue fasciculations, gynecomastia, increased serum testosterone and creatine kinase levels. The peculiarities of the case were the gynecomastia under the age of 7, development of fasciculations at the age of 11 and appearance of hard muscle stiffness with delayed muscle relaxation after voluntary contraction at the age of 15, which resembled typical myotonia. Electromyography showed few signs of mild without myotonic discharge, contrasting with giant motor unit potentials and reduced recruitment. The cause of myotonia-like symptom without myotonic discharge as a feature of skeletal muscles disorder is discussed with the modern view of spinal and bulbar muscular atrophy as a multisystem genetic pathology.

Association of Three Different Mutations in the CLCN1 Gene Modulating the Phenotype in a Consanguineous Family with Myotonia Congenita

2021 ◽  
Author(s):  
Lucas Santos Souza ◽  
Priscila Calyjur ◽  
Antonio Fernando Ribeiro ◽  
Juliana Gurgel-Giannetti ◽  
Rita Cassia Mingroni Pavanello ◽  
...  
Keyword(s):  
Consanguineous Family ◽  
Myotonia Congenita ◽  
Clcn1 Gene

scholarly journals A rare large duplication of MLH1 identified in Lynch syndrome

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Abhishek Kumar ◽  
Nagarajan Paramasivam ◽  
Obul Reddy Bandapalli ◽  
Matthias Schlesner ◽  
Tianhui Chen ◽  
...  
Keyword(s):  
Amino Acid ◽  
Lynch Syndrome ◽  
Splice Site ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Splice Donor Site ◽  
Laboratory Diagnostics ◽  
Mmr Genes ◽  
Base Pair Deletion ◽  
Splice Site Variant

Abstract Background The most frequently identified strong cancer predisposition mutations for colorectal cancer (CRC) are those in the mismatch repair (MMR) genes in Lynch syndrome. Laboratory diagnostics include testing tumors for immunohistochemical staining (IHC) of the Lynch syndrome-associated DNA MMR proteins and/or for microsatellite instability (MSI) followed by sequencing or other techniques, such as denaturing high performance liquid chromatography (DHPLC), to identify the mutation. Methods In an ongoing project focusing on finding Mendelian cancer syndromes we applied whole-exome/whole-genome sequencing (WES/WGS) to 19 CRC families. Results Three families were identified with a pathogenic/likely pathogenic germline variant in a MMR gene that had previously tested negative in DHPLC gene variant screening. All families had a history of CRC in several family members across multiple generations. Tumor analysis showed loss of the MMR protein IHC staining corresponding to the mutated genes, as well as MSI. In family A, a structural variant, a duplication of exons 4 to 13, was identified in MLH1. The duplication was predicted to lead to a frameshift at amino acid 520 and a premature stop codon at amino acid 539. In family B, a 1 base pair deletion was found in MLH1, resulting in a frameshift and a stop codon at amino acid 491. In family C, we identified a splice site variant in MSH2, which was predicted to lead loss of a splice donor site. Conclusions We identified altogether three pathogenic/likely pathogenic variants in the MMR genes in three of the 19 sequenced families. The MLH1 variants, a duplication of exons 4 to 13 and a frameshift variant, were novel, based on the InSiGHT and ClinVar databases; the MSH2 splice site variant was reported by a single submitter in ClinVar. As a variant class, duplications have rarely been reported in the MMR gene literature, particularly those covering several exons.

A common founder effect of the splice site variant c.-23 + 1G > A in GJB2 gene causing autosomal recessive deafness 1A (DFNB1A) in Eurasia

2021 ◽  
Author(s):  
Aisen V. Solovyev ◽  
Alena Kushniarevich ◽  
Elena Bliznetz ◽  
Marita Bady-Khoo ◽  
Maria R. Lalayants ◽  
...  
Keyword(s):  
Splice Site ◽  
Founder Effect ◽  
Autosomal Recessive ◽  
Gjb2 Gene ◽  
C 23 ◽  
Common Founder ◽  
Splice Site Variant

Genetic analysis of Pycr1 and Pycr2 in mice

Genetics ◽  
2021 ◽  
Author(s):  
Morgane G Stum ◽  
Abigail L D Tadenev ◽  
Kevin L Seburn ◽  
Kathy E Miers ◽  
Pak P Poon ◽  
...  
Keyword(s):  
Neuromuscular Disorders ◽  
Subcutaneous Fat ◽  
Mutant Mice ◽  
Loss Of Function ◽  
Proline Biosynthesis ◽  
Cell Counts ◽  
Chemically Induced ◽  
White Blood Cell Counts ◽  
Redundant Functions ◽  
Altered Lipid

Abstract The final step in proline biosynthesis is catalyzed by three pyrroline-5-carboxylate reductases, PYCR1, PYCR2, and PYCR3, which convert pyrroline-5-carboxylate (P5C) to proline. Mutations in human PYCR1 and ALDH18A1 (P5C Synthetase) cause Cutis Laxa (CL), whereas mutations in PYCR2 cause hypomyelinating leukodystrophy 10 (HLD10). Here, we investigated the genetics of Pycr1 and Pycr2 in mice. A null allele of Pycr1 did not show integument or CL-related phenotypes. We also studied a novel chemically-induced mutation in Pycr2. Mice with recessive loss-of-function mutations in Pycr2 showed phenotypes consistent with neurological and neuromuscular disorders, including weight loss, kyphosis, and hind-limb clasping. The peripheral nervous system was largely unaffected, with only mild axonal atrophy in peripheral nerves. A severe loss of subcutaneous fat in Pycr2 mutant mice is reminiscent of a CL-like phenotype, but primary features such as elastin abnormalities were not observed. Aged Pycr2 mutant mice had reduced white blood cell counts and altered lipid metabolism, suggesting a generalized metabolic disorder. PYCR1 and -2 have similar enzymatic and cellular activities, and consistent with previous studies, both were localized in the mitochondria in fibroblasts. Both PYCR1 and -2 were able to complement the loss of Pro3, the yeast enzyme that converts P5C to proline, confirming their activity as P5C reductases. In mice, Pycr1; Pycr2 double mutants were sub-viable and unhealthy compared to either single mutant, indicating the genes are largely functionally redundant. Proline levels were not reduced, and precursors were not increased in serum from Pycr2 mutant mice or in lysates from skin fibroblast cultures, but placing Pycr2 mutant mice on a proline-free diet worsened the phenotype. Thus, Pycr1 and -2 have redundant functions in proline biosynthesis, and their loss makes proline a semi-essential amino acid. These findings have implications for understanding the genetics of CL and HLD10, and for modeling these disorders in mice.

A splice-site variant in ANKRD11 associated with classical KBG syndrome

2017 ◽  
Vol 173 (10) ◽  
pp. 2844-2846 ◽  
Author(s):  
Karen J. Low ◽  
Alison Hills ◽  
Maggie Williams ◽  
Celia Duff-Farrier ◽  
Shane McKee ◽  
...  
Keyword(s):  
Splice Site ◽  
Kbg Syndrome ◽  
Splice Site Variant

scholarly journals A splice site variant in INPP5E causes diffuse cystic renal dysplasia and hepatic fibrosis in dogs

PLoS ONE ◽  
2018 ◽  
Vol 13 (9) ◽  
pp. e0204073 ◽  
Author(s):  
Kati J. Dillard ◽  
Marjo K. Hytönen ◽  
Daniel Fischer ◽  
Kimmo Tanhuanpää ◽  
Mari S. Lehti ◽  
...  
Keyword(s):  
Hepatic Fibrosis ◽  
Splice Site ◽  
Renal Dysplasia ◽  
Cystic Renal Dysplasia ◽  
Splice Site Variant

scholarly journals Muscle contracture and passive mechanics in cerebral palsy

2019 ◽  
Vol 126 (5) ◽  
pp. 1492-1501 ◽  
Author(s):  
Richard L. Lieber ◽  
Jan Fridén
Keyword(s):  
Extracellular Matrix ◽  
Cerebral Palsy ◽  
Satellite Cells ◽  
Neuromuscular Disorders ◽  
Light And Electron Microscopy ◽  
Cell Types ◽  
Underlying Mechanism ◽  
Muscle Stiffness ◽  
Muscle Satellite Cells ◽  
Cord Injury

Skeletal muscle contractures represent the permanent shortening of a muscle-tendon unit, resulting in loss of elasticity and, in extreme cases, joint deformation. They may result from cerebral palsy, spinal cord injury, stroke, muscular dystrophy, and other neuromuscular disorders. Contractures are the prototypic and most severe clinical presentation of increased passive mechanical muscle force in humans, often requiring surgical correction. Intraoperative experiments demonstrate that high muscle passive force is associated with sarcomeres that are abnormally stretched, although otherwise normal, with fewer sarcomeres in series. Furthermore, changes in the amount and arrangement of collagen in the extracellular matrix also increase muscle stiffness. Structural light and electron microscopy studies demonstrate that large bundles of collagen, referred to as perimysial cables, may be responsible for this increased stiffness and are regulated by interaction of a number of cell types within the extracellular matrix. Loss of muscle satellite cells may be related to changes in both sarcomeres and extracellular matrix. Future studies are required to determine the underlying mechanism for changes in muscle satellite cells and their relationship (if any) to contracture. A more complete understanding of this mechanism may lead to effective nonsurgical treatments to relieve and even prevent muscle contractures.

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