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Exome sequencing of autosomal recessive progressive external ophthalmoplegia (arPEO)

ABSTRACT:

Progressive external ophthalmoplegia (PEO) is an inherited mitochondrial disease that follows either autosomal dominant or recessive forms of inheritance (adPEO or arPEO). AdPEO is a genetically heterogeneous disease and several genes including POLG1 and C10orf2/Twinkle have been identified as responsible genes. On the other hand, POLG1 was the only established gene causing arPEO with mitochondrial DNA deletions. We previously reported a case of PEO with unidentified genetic etiology. The patient was born of a first-cousin marriage. Therefore, the recessive form of inheritance was suspected. To identify the disease causing variant in this patient, we subjected the patient's DNA to whole-exome sequencing and narrowed down the candidate variants using public data and runs of homozygosity analysis.

PROVIDER: phs000392.v1.p1 | EGA |

REPOSITORIES: EGA

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Exome sequencing identifies a novel missense variant in RRM2B associated with autosomal recessive progressive external ophthalmoplegia.

Takata Atsushi A Kato Maiko M Nakamura Masayuki M Yoshikawa Takeo T Kanba Shigenobu S Sano Akira A Kato Tadafumi T

Genome biology 20110928 9

<h4>Background</h4>Whole-exome sequencing using next-generation technologies has been previously demonstrated to be able to detect rare disease-causing variants. Progressive external ophthalmoplegia (PEO) is an inherited mitochondrial disease that follows either autosomal dominant or recessive forms of inheritance (adPEO or arPEO). AdPEO is a genetically heterogeneous disease and several genes, including POLG1 and C10orf2/Twinkle, have been identified as responsible genes. On the other hand, POL ...[more]

PMID: 21951382

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Exome Sequencing of arPEO

Project description:Progressive external ophthalmoplegia (PEO) is an inherited mitochondrial disease that follows either autosomal dominant or recessive forms of inheritance (adPEO or arPEO). AdPEO is a genetically heterogeneous disease and several genes including POLG1 and C10orf2/Twinkle have been identified as responsible genes. On the other hand, POLG1 was the only established gene causing arPEO with mitochondrial DNA deletions. We previously reported a case of PEO with unidentified genetic etiology. The patient was born of a first-cousin marriage. Therefore, the recessive form of inheritance was suspected. To identify the disease causing variant in this patient, we subjected the patient's DNA to whole-exome sequencing and narrowed down the candidate variants using public data and runs of homozygosity analysis.

| phs000392 | dbGaP

Cas9-guided haplotyping of three truncation variants in autosomal recessive disease

Project description:An autosomal recessive disease is caused by biallelic loss-of-function mutations. However, when more than two disease-causing variants are found in a patient’s gene, it has been challenging to determine which two of the variants are responsible for the disease phenotype. To decipher the pathogenic variants by precise haplotyping, we applied nanopore Cas9-targeted sequencing (nCATS) to three truncation COL7A1 variants detected in a patient with recessive dystrophic epidermolysis bullosa (EB). The distance between the most 5’ and 3’ variants was around 19 kb at the level of genomic DNA. nCATS successfully delineated that the most 5’ and 3’ variants were located in one allele while the variant in between was in the other allele. Intriguingly, the proband’s mother, who was phenotypically intact, was heterozygous for the allele that harbored the two truncation variants, which could otherwise be misinterpreted as those of typical recessive dystrophic EB. Our study illuminates nCATS as a useful tool to determine haplotypes of complicated genetic cases. Haplotyping of multiple variants in a gene can tell which variant should be therapeutically targeted when nucleotide-specific gene therapy is applied.

2022-05-02 | GSE196673 | GEO

Exome Sequencing in Autosomal Recessive Progressive External Ophthalmoplegia

Project description:Exome Sequencing in Autosomal Recessive Progressive External Ophthalmoplegia

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Genotyping of autosomal recessive type of limb-girdle muscular dystrophies

Project description:26 limb-girdle muscular dystrophy patients from Latvia and 34 patients from Lithuania with clinical symptoms of limb-girdle muscular dystrophies, along with 204 healthy unrelated controls were genotyped for 96 most frequent known limb-girdle muscular dystrophies causing mutations for the region, using VeraCode GoldenGate system. More information can be found in article Robust genotyping tool for autosomal recessive type of limb-girdle muscular dystrophies in BMC Musculoskeletal Disorders by I. Inashkina et al.

2016-04-28 | E-MTAB-4662 | biostudies-arrayexpress

Generation and characterization of NGLY1 patient-derived midbrain organoids

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2023-02-03 | GSE224294 | GEO

Autosomal recessive TPP2 mutations cause a new human immunodeficiency

Project description:To define a genetic syndrome of combined immunodeficiency, severe autoimmunity, and developmental delay, 4 patients from two families who had similar syndromic features were studied. To identify disease-causing mutations, we performed whole exome sequencing for one patient and her healthy parent from Family 1 and also for one patient from Family 2. Disease segregated with novel autosomal recessive mutations in a single gene, tripeptidyl-peptidase II (TPP2) gene. The result defines a new human metabolic immunodeficiency.

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Parkinson Phenotype in Aged PINK1-Deficient Mice Is Accompanied by Progressive Mitochondrial Dysfunction in Absence of Neurodegeneration

Project description:Parkinson's disease (PD) is an adult-onset movement disorder of largely unknown etiology. We have previously shown that loss-of-function mutations of the mitochondrial protein kinase PINK1 (PTEN induced putative kinase 1) cause the recessive PARK6 variant of PD. Now we generated a PINK1 deficient mouse and observed several novel phenotypes: A progressive reduction of weight and of locomotor activity selectively for spontaneous movements occurred at old age. As in PD, abnormal dopamine levels in the aged nigrostriatal projection accompanied the reduced movements. Possibly in line with the PARK6 syndrome but in contrast to sporadic PD, a reduced lifespan, dysfunction of brainstem and sympathetic nerves, visible aggregates of M-NM-1-synuclein within Lewy bodies or nigrostriatal neurodegeneration were not present in aged PINK1-deficient mice. However, we demonstrate PINK1 mutant mice to exhibit a progressive reduction in mitochondrial preprotein import correlating with defects of core mitochondrial functions like ATP-generation and respiration. In contrast to the strong effect of PINK1 on mitochondrial dynamics in Drosophila melanogaster and in spite of reduced expression of fission factor Mtp18, we show reduced fission and increased aggregation of mitochondria only under stress in PINK1-deficient mouse neurons. Thus, aging Pink1M-bM-^HM-^R/M-bM-^HM-^R mice show increasing mitochondrial dysfunction resulting in impaired neural activity similar to PD, in absence of overt neuronal death. Transcriptome microarray data of Pink1-/- mouse brains in absence of a stressor, even at old age, show remarkably sparse dysregulations. See Gispert-S et al 2009 PLOS ONE. Factorial design comparing Pink1 knock-out mice with wild type littermates in three different tissues (striatum, midbrain, cerebellum at four different timepoints (6, 12, 14 weeks, and 18 month)

2014-11-04 | E-GEOD-60413 | biostudies-arrayexpress

Ancestral allele of DNA polymerase gamma modifies antiviral tolerance

Project description:Mitochondria are arising as critical modulators of antiviral tolerance by releasing mtDNA/mtRNA fragments to cytoplasm upon infection, activating virus sensors and type-I interferon response. The relevance of these mechanisms for mitochondrial diseases remains understudied. Here, we investigated mitochondrial recessive ataxia syndrome (MIRAS), caused by a common European founder mutation in DNA polymerase gamma (POLG1). The patients homozygous for the MIRAS variant p.W748S show exceptionally variable ages-of-onset and symptoms, indicating unknown modifying factors contributing to disease manifestation. We report that the mitochondrial DNA (mtDNA) replicase POLG1 has a role in antiviral defence mechanisms to double-stranded DNA and positive-strand RNA virus infections (HSV-1, TBEV, SARS-CoV-2) and its p.W748S variant dampens innate immune responses. Our patient and knock-in mouse data show that p.W748S compromises mtDNA replisome stability, causing mtDNA depletion, aggravated by virus infection. Low mtDNA and mtRNA release to cytoplasm and slow interferon response in MIRAS allow an early replicative advantage for viruses, leading to augmented pro-inflammatory response, subacute loss of GABAergic neurons, liver inflammation and necrosis. A population databank of ~300,000 Finns demonstrates enrichment of immunodeficient traits in p.W748S carriers. Our evidence suggests that POLG1 defects compromise antiviral tolerance, triggering epilepsy and liver disease. The finding has important implications to mitochondrial disease spectrum, including epilepsy, ataxia, and parkinsonism.

2024-01-19 | GSE249432 | GEO

Cas9-guided haplotyping of three truncation variants in autosomal recessive disease

Project description:Cas9-guided haplotyping of three truncation variants in autosomal recessive disease

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Expanding the phenotype of NUP85 mutations beyond nephrotic syndrome to Primary autosomal recessive microcephaly and Seckel syndrome spectrum disoders

Project description:Primary autosomal recessive microcepahly and Seckel syndrome spectrum disodrers (MCPH-SCKS) include a heterogenous group of autosomal recessive inherited diseases characterized by primary (congenital) microcephaly, the absence of visceral abnormalities and a variable degree of cognitive impairment, short stature and facial dysmorphism. Recently, biallelic mutations in the nuclear pore complex (NPC) component nucleoporin 85 gene (NUP85) were reported to cause steroid-resistant nephrotic syndrome (SRNS). Here we report that homozygous mutations in NUP85 can also cause MCPH-SCKS without SRNS and thereby expand the phenotypic spectrum of NUP85-linked diseases. Structural analysis predicts the identified NUP85 mutation to have neither an effect on NPC architecture nor on its interaction with other NUPs. We show that mutant NUP85 is, however, associated with a reduced number of NPCs, abnormal mitotic spindle morphology, altered expression levels of protein involved in of cytoskeletal dynamics and decreased cell viability in patient cells. These altered biological processes can explain the disease-causative nature of the mutant NUP85 associated with the human phenotype. Our results also indicates the link of common cellular mechanism involved in the MCPH-SCKS spectrum disorders and NUP85-associated diseases. In addition to the previous studies, our results broadened the phenotype spectrum of NUP85-specific human disease and emphasizes a role of NUP85 in the development of the nervous system.

2022-08-11 | PXD018838 | Pride

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