Browse
Submit Data
Databases
API
Help

Dataset Information

18 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Identification of a novel MICU1 nonsense variant causes myopathy with extrapyramidal signs in an Iranian consanguineous family.

ABSTRACT:

Background

Ca²⁺ as a universal second messenger regulates basic biological functions including cell cycle, cell proliferation, cell differentiation, and cell death. Lack of the protein mitochondrial calcium uptake1 (MICU1), which has been regarded as a gatekeeper of Ca ions, leads to the abnormal mitochondrial Ca²⁺ handling, excessive production of reactive oxygen species (ROS), and increased cell death. Mutations in MICU1 gene causes a very rare neuromuscular disease, myopathy with extrapyramidal signs (MPXPS), due to primary alterations in mitochondrial calcium signaling which demonstrates the key role of mitochondrial Ca²⁺ uptake. To date, 13 variants have been reported in MICU1 gene in 44 patients presented with the vast spectrum of symptoms.

Case presentation

Here, we report a 44-year-old Iranian patient presented with learning disability, muscle weakness, easy fatigability, reduced tendon reflexes, ataxia, gait disturbance, elevated hepatic transaminases, elevated serum creatine kinase (CK), and elevated lactate dehydrogenase (LDH). We identified a novel nonsense variant c.385C>T; p.(R129*) in MICU1 gene by whole exome sequencing (WES) and segregation analysis.

Conclusions

Our finding along with previous studies provides more evidence on the clinical presentation of the disease caused by pathogenic mutations in MICU1. Finding more variants and expanding the spectrum of the disease increases the diagnostic rate of molecular testing in screening of this kind of diseases and in turn improves the quality of counseling for at risk couples and helps them to minimize the risks of having affected children.

SUBMITTER: Bitarafan F

PROVIDER: S-EPMC8107061 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Reporting a rare form of myopathy, myopathy with extrapyramidal signs, in an Iranian family using next generation sequencing: a case report.

Project description:BACKGROUND:Myopathy with extrapyramidal signs (MPXPS) is an autosomal recessive mitochondrial disorder which is caused by mutation in mitochondrial calcium uptake 1 (MICU1) gene located on chromosome 10q22.1. Next Generation Sequencing (NGS) technology is the most effective method for identification of pathogenic variants with the ability to overcome some limitations which Sanger sequencing may encountered. There are few reports on this rare disease around the world and here in this study we first revealed genetic identification of two affected individuals in an Iranian family with a novel mutation. CASE PRESENTATION:The proband was a 5-year-old girl from consanguenous parents. She was first clinically suspicious of affected with limb-girdle muscular dystrophy (LGMD). Muscle biopsy studies and autozygosity mapping, using four short tandem repeat (STR) markers linked to 6 genes of the most prevalent forms of LGMD, ruled out calpainopathy, dysferlinopathy, and sarcoglycanopathis. DNA sample of the proband was sent for NGS. Whole exome sequencing (WES) revealed a novel mutation c.1295delA in exon 13 of MICU1 gene. This homozygous deletion creates a frameshift and a premature stop codon downstream of canonical EF4 calcium binding motif of MICU1. According to the American College of Medical Genetics and Genomics (ACMG) guidline for sequence interpretation, this variant was a pathogenic one. Sanger sequencing in all family members confirmed the results of the WES. CONCLUSIONS:This study was the first report of MPXPS in Iranian population which also revealed a novel mutation in the MICU1 gene.

| S-EPMC7158096 | biostudies-literature

Developmental brain abnormalities and acute encephalopathy in a patient with myopathy with extrapyramidal signs secondary to pathogenic variants in MICU1.

Project description:Mitochondria play a variety of roles in the cell, far beyond their widely recognized role in ATP generation. One such role is the regulation and sequestration of calcium, which is done with the help of the mitochondrial calcium uniporter (MCU) and its regulators, MICU1 and MICU2. Genetic variations in MICU1 and MICU2 have been reported to cause myopathy, developmental disability and neurological symptoms typical of mitochondrial disorders. The symptoms of MICU1/2 deficiency have generally been attributed to calcium regulation in the metabolic and biochemical roles of mitochondria. Here, we report a female child with heterozygous MICU1 variants and multiple congenital brain malformations on MRI. Specifically, she shows anterior perisylvian polymicrogyria, dysmorphic basal ganglia, and cerebellar dysplasia in addition to white matter abnormalities. These novel findings suggest that MICU1 is necessary for proper neurodevelopment through a variety of potential mechanisms, including calcium-mediated regulation of the neuronal cytoskeleton, Miro1-MCU complex-mediated mitochondrial movement, or enhancing ATP production. This case provides new insight into the molecular pathogenesis of MCU dysfunction and may represent a novel diagnostic feature of calcium-based mitochondrial disease.

| S-EPMC7203647 | biostudies-literature

A homozygote variant in the tRNA splicing endonuclease subunit 54 causes pontocerebellar hypoplasia in a consanguineous Iranian family.

Project description:BackgroundHomozygous loss-of-function mutations in TSEN54 (tRNA splicing endonuclease subunit 54; OMIM: 608755) cause different types of pontocerebellar hypoplasias (PCH) including PCH2, PCH4, and PCH5. The study aimed to determine the possible genetic factors contributing to PCH phenotypes in two affected male infants in an Iranian family.MethodsWe subjected two affected individuals in a consanguineous Iranian family. To systematically investigate the susceptible gene(s), whole-exome sequencing was performed on the proband and a novel identified variant was confirmed by Sanger sequencing. We also analyzed 26 relatives in three generations using PCR-restriction fragment length polymorphism (PCR-RFLP) followed and confirmed by Sanger sequencing.ResultsPhysical and medical examinations confirmed PCH in the patients. Besides, the proband showed bilateral moderate sensorineural hearing loss and structural heart defects as the novel phenotypes. The molecular findings also verified that two affected individuals were homozygote for the novel synonymous variant, NM_207346.2: c.1170G>A; p.(Val390Val), in TSEN54. PCR-RFLP and Sanger sequencing elucidated that the parents and 16 relatives were heterozygote for the novel variant.ConclusionWe identified a novel synonymous variant, c.1170G>A, in TSEN54 associated with PCH in an Iranian family. Based on this study, we strongly suggest using "TSENopathies" to show the overlapped phenotypes among different types of PCH resulted from TSEN causative mutations.

| S-EPMC7549571 | biostudies-literature

A Novel Homozygous Frameshift Variant in XYLT2 Causes Spondyloocular Syndrome in a Consanguineous Pakistani Family.

Project description:We report on three new patients with spondyloocular syndrome (SOS) in a consanguineous Pakistani family. All three patients present progressive generalized osteoporosis, short stature, recurrent fractures, hearing loss and visual impairments. WES revealed a novel homozygous frameshift variant in exon 11 of XYLT2 (NG 012175.1, NP_071450.2) resulting in loss of evolutionary conserved amino acid sequences (840 - 865/865) at C-terminus p.R840fs?115. Sanger Sequencing confirmed the presence of the novel homozygous mutation in all three patients while the parents were heterozygous carriers of the mutation, in accordance with an autosomal recessive inheritance pattern. Only nine variants worldwide have previously been reported in XYLT2 in patients with SOS phenotype. These three patients with novel homozygous variant extend the genotypic and phenotypic spectrum of SOS.

| S-EPMC6411848 | biostudies-literature

A Homozygous Nonsense Thyroid Peroxidase Mutation (R540X) Consistently Causes Congenital Hypothyroidism in Two Siblings Born to a Consanguineous Family.

Project description:Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder, and mutations in the thyroid peroxidase (TPO) gene have been reported to cause the disease. Our aim in this study was to determine the genetic basis of CH in two affected children coming from a consanguineous family.First, we investigated the potential genetic linkage of the family to any known CH locus using microsatellite markers and then screened for mutations in the linked gene by Sanger sequencing. By using next-generation sequencing, we also checked if any other mutation was present in the remaining 10 causative CH genes.The family showed potential linkage to the TPO gene, and we detected a homozygous nonsense mutation (R540X) in both cases. The two patients had total iodide organification defect (TIOD). Both the microsatellite marker haplotypes and the mutation segregated with the disease status in the family, i.e. all healthy subjects were either heterozygous carriers or homozygous wild-type, confirming the pathogenic nature of the mutation. Neither was the mutation present in any of the 400 control chromosomes nor were there any other mutations in the remaining causative CH genes.This study proves the pathogenicity of R540X mutation and demonstrates the strong genotype/phenotype correlation associated with this mutation. It also highlights the power of working with familial cases in revealing the molecular basis of CH and in establishing accurate genotype/phenotype relationships associated with disease causing mutations.

| S-EPMC4805212 | biostudies-literature

Identification of a novel nonsense mutation in kyphoscoliosis peptidase gene in an Iranian patient with myofibrillar myopathy.

Project description:Myofibrillar myopathies (MFMs) are rare genetic and slowly progressive neuromuscular disorders. Several pathogenic mutations have been reported in MFM-related genes including DES, CRYAB, MYOT, LDB3 or ZASP, FLNC, BAG3, FHL1 and DNAJB6. Although MFMs is commonly inherited in an autosomal dominant manner, the inheritance pattern and novel mutated genes are not thoroughly elucidated in some cases. Here, we report discovery of a novel nonsense mutation in a 29-year-old Iranian male patient with motor disorders and deformity in his lower limbs. His parents are second cousins. Hereditary Motor Sensory Neuropathy as initial genetic diagnosis was ruled out. Whole exome sequencing using NGS on Illumina HiSeq4000 platform was performed to identify the disease and possible mutated gene(s). Our data analysis identified a homozygous nonsense unreported c.C415T (p.R139X) variant on kyphoscoliosis peptidase (KY) gene (NM_178554: exon4). Sanger sequencing of this mutation has been performed for his other related family members. Sequencing and segregation analysis was confirmed the NGS results and autosomal recessive inheritance pattern of the disease.

| S-EPMC6303478 | biostudies-literature

A novel homozygous variant of GPR98 causes usher syndrome type IIC in a consanguineous Chinese family by next generation sequencing.

Project description:BACKGROUND:Usher syndrome (USH) is a common heterogeneous retinopathy and a hearing loss (HL) syndrome. However, the gene causing Usher syndrome type IIC (USH2C) in a consanguineous Chinese pedigree is unknown. METHODS:We performed targeted next-generation sequencing analysis and Sanger sequencing to explore the GPR98 mutations in a USH2C pedigree that included a 32-year-old male patient from a consanguineous marriage family. Western blot verified the nonsense mutation. RESULTS:To identify disease-causing gene variants in a consanguineous Chinese pedigree with USH2C, DNA from proband was analyzed using targeted next generation sequencing (NGS). The patient was clinically documented as a possible USH2 by a comprehensive auditory and ophthalmology evaluation. We succeeded in identifying the deleterious, novel, and homologous variant, c.6912dupG (p.Leu2305Valfs*4), in the GPR98 gene (NM_032119.3) that contributes to the progression of USH2C. Variant detected by targeted NGS was then confirmed and co-segregation was conducted by direct Sanger sequencing. Western blot verified losing almost two-thirds of its amino acid residues, including partial Calx-beta, whole EPTP and 7TM-GPCRs at the C-terminus of GPR98. Furthermore, our results highlighted that this p.Leu2305Valfs*4 variant is most likely pathogenic due to a large deletion at the seven-transmembrane G protein-coupled receptors (7TM-GPCRs) domain in GPR98 protein, leading to significantly decreased functionality and complex stability. CONCLUSIONS:These findings characterized the novel disease causativeness variant in GPR98 and broaden mutation spectrums, which could predict the pathogenic progression of patient with USH2C, guide diagnosis and treatment of this disease; and provide genetic counseling and family planning for consanguineous marriage pedigree in developing countries, including China.

| S-EPMC5996530 | biostudies-literature

A Novel Missense Mutation in the ALDH13 Gene Causes Anophthalmia in Two Unrelated Iranian Consanguineous Families.

Project description:Anophthalmia or microphthalmia (A/M) is a rare group of congenital/developmental ocular malformations, characterized by absent or small eye within the orbit affecting one or both eyes. It has complex etiology with chromosomal, monogenic with high heterogeneity, and environmental causes. We performed genome SNP-array analysis followed by autozygosity mapping and sequencing in the members of two families in which three individuals are suffering from severe bilateral anophthalmia. The genetic analysis revealed a novel missense c.709G>A mutation in exon 7 of ALDH1A3 (aldehyde dehydrogenase 1 family member A3), causing a substitution of glycine (Gly) to arginine (Arg) at residue 237. This study consolidates the importance of ALDH1A3 gene screening in autosomal recessive anophthalmia. This variation may also be suggestive of a founder effect in the southeastern area of Iran.

| S-EPMC5581554 | biostudies-literature

Homozygous WNT3 mutation causes tetra-amelia in a large consanguineous family.

Project description:Tetra-amelia is a rare human genetic disorder characterized by complete absence of all four limbs and other anomalies. We studied a consanguineous family with four affected fetuses displaying autosomal recessive tetra-amelia and craniofacial and urogenital defects. By homozygosity mapping, the disease locus was assigned to chromosome 17q21, with a maximum multipoint LOD score of 2.9 at markers D17S931, D17S1785, D17SS1827, and D17S1868. Further fine mapping defined a critical interval of approximately 8.9 Mb between D17S1299 and D17S797. We identified a homozygous nonsense mutation (Q83X) in the WNT3 gene in affected fetuses of the family. WNT3, a human homologue of the Drosophila wingless gene, encodes a member of the WNT family known to play key roles in embryonic development. The Q83X mutation truncates WNT3 at its amino terminus, suggesting that loss of function is the most likely cause of the disorder. Our findings contrast with the observation of early lethality in mice homozygous for null alleles of Wnt3. To our knowledge, this is the first report of a mutation in a WNT gene associated with a Mendelian disorder. The identification of a WNT3 mutation in tetra-amelia indicates that WNT3 is required at the earliest stages of human limb formation and for craniofacial and urogenital development.

| S-EPMC1182269 | biostudies-literature

A novel pathogenic variant in the LRTOMT gene causes autosomal recessive non-syndromic hearing loss in an Iranian family.

Project description:BackgroundHearing loss (HL) is the most common sensorineural disorder with high phenotypic and genotypic heterogeneity, which negatively affects life quality. Autosomal recessive non-syndromic hearing loss (ARNSHL) constitutes a major share of HL cases. In the present study, Whole exome sequencing (WES) was applied to investigate the underlying etiology of HL in an Iranian patient with ARNSHL.MethodsA proband from an Iranian consanguineous family was examined via WES, following GJB2 sequencing. WES was utilized to find possible genetic etiology of the disease. Various Bioinformatics tools were used to assess the pathogenicity of the variants. Co-segregation analysis of the candidate variant was carried out. Interpretation of variants was performed according to the American College of Medical Genetics and Genomics (ACMG) guidelines.ResultsWES results showed a novel frameshift (16 bp deletion) variant (p.Ala170Alafs*20) in the LRTOMT gene. This variant, which resides in exon 6, was found to be co-segregating in the family. It fulfils the criteria set by the ACMG guidelines of being pathogenic.ConclusionHere, we report successful application of WES to identify the molecular pathogenesis of ARNSHL, which is a genetically heterogeneous disorder, in a patient with ARNSHL.

| S-EPMC7285524 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data