A recessive variant in TFAM causes mtDNA depletion associated with primary ovarian insufficiency, seizures, intellectual disability and hearing loss

Ullah, Farid; Rauf, Waqar; Khan, Kamal; Khan, Sheraz; Bell, Katrina M.; Oliveira, Vanessa Cristina de; Tariq, Muhammad; Bakhshalizadeh, Shabnam; Touraine, Philippe; Katsanis, Nicholas; Sinclair, Andrew H.; He, Sijie; Tucker, Elena J.; Baig, Shahid Mahmood; Davis, Erica E.

doi:10.1007/s00439-021-02380-2

Cited by 17 publications

(10 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In these experiments, co-expression of the wt protein confounds interpretation and makes impossible unambiguous attribution of a phenotype to a specific TFAM mutation. Therefore, the only reliable information regarding the effects of mutations in human TFAM (hTFAM) on human mtDNA (hmtDNA) replication in situ available to date is derived from two pedigrees with mtDNA depletion [ 26 , 27 ]. Here, we developed a GeneSwap approach that circumvents many of these limitations.…”

Section: Introductionmentioning

confidence: 99%

A Method for In Situ Reverse Genetic Analysis of Proteins Involved mtDNA Replication

Kozhukhar

Spadafora

Rodriguez

et al. 2022

Cells

View full text Add to dashboard Cite

The unavailability of tractable reverse genetic analysis approaches represents an obstacle to a better understanding of mitochondrial DNA replication. Here, we used CRISPR-Cas9 mediated gene editing to establish the conditional viability of knockouts in the key proteins involved in mtDNA replication. This observation prompted us to develop a set of tools for reverse genetic analysis in situ, which we called the GeneSwap approach. The technique was validated by identifying 730 amino acid (aa) substitutions in the mature human TFAM that are conditionally permissive for mtDNA replication. We established that HMG domains of TFAM are functionally independent, which opens opportunities for engineering chimeric TFAMs with customized properties for studies on mtDNA replication, mitochondrial transcription, and respiratory chain function. Finally, we present evidence that the HMG2 domain plays the leading role in TFAM species-specificity, thus indicating a potential pathway for TFAM-mtDNA evolutionary co-adaptations.

show abstract

Section: Introductionmentioning

confidence: 99%

A Method for In Situ Reverse Genetic Analysis of Proteins Involved mtDNA Replication

Kozhukhar

Spadafora

Rodriguez

et al. 2022

Cells

View full text Add to dashboard Cite

show abstract

“…In addition to point mutations of nuclear genes, CNVs and mtDNA variants are also responsible for part of neurodevelopmental disorders ( Lam et al, 2019 ; Ullah et al, 2021 ; Silva et al, 2022 ; Sun et al, 2022 ). D’Gama has reported a case (AN00090) harboring a germline missense mutations in SETD2 predicted to be deleterious (responsible for ASD) and a 15q deletion consistent with her diagnosis of Angelman syndrome ( D'Gama et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

A novel SETD2 variant causing global development delay without overgrowth in a Chinese 3-year-old boy

Liu

Wan

et al. 2023

Front. Genet.

View full text Add to dashboard Cite

Background: Luscan-Lumish syndrome is characterized by macrocephaly, postnatal overgrowth, intellectual disability (ID), developmental delay (DD), which is caused by heterozygous SETD2 (SET domain containing 2) mutations. The incidence of Luscan-Lumish syndrome is unclear. The study was conducted to provide a novel pathogenic SETD2 variant causing atypical Luscan-Lumish syndrome and review all the published SETD2 mutations and corresponding symptoms, comprehensively understanding the phenotypes and genotypes of SETD2 mutations.Methods: Peripheral blood samples of the proband and his parents were collected for next-generation sequencing including whole-exome sequencing (WES), copy number variation (CNV) detection and mitochondrial DNA sequencing. Identified variant was verified by Sanger sequencing. Conservative analysis and structural analysis were performed to investigate the effect of mutation. Public databases such as PubMed, Clinvar and Human Gene Mutation Database (HGMD) were used to collect all cases with SETD2 mutations.Results: A novel pathogenic SETD2 variant (c.5835_c.5836insAGAA, p. A1946Rfs*2) was identified in a Chinese 3-year-old boy, who had speech and motor delay without overgrowth. Conservative analysis and structural analysis showed that the novel pathogenic variant would loss the conserved domains in the C-terminal region and result in loss of function of SETD2 protein. Frameshift mutations and non-sense mutations account for 68.5% of the total 51 SETD2 point mutations, suggesting that Luscan-Lumish syndrome is likely due to loss of function of SETD2. But we failed to find an association between genotype and phenotype of SETD2 mutations.Conclusion: Our findings expand the genotype-phenotype knowledge of SETD2-associated neurological disorder and provide new evidence for further genetic counselling.

show abstract

“…There are a number of mitochondrial disease genes that have been found to cause milder adult-onset disease, and POI is a common feature of such conditions. Examples include POI in association with sensorineural hearing loss due to variants in TFAM ( 51 , 52 ), LARS2 ( 53 ), HARS2 ( 54 ), ERAL1 ( 55 ), CLPP ( 48 ), or TWNK ( 56 ); POI in association with adult-onset neurodegeneration due to variants in AARS2 ( 57 ) or LARS2 ( 58 ); or POI in association with vision loss or parkinsonism due to variants in TWNK ( 59 , 60 ). Many of these genes were first identified in association with severe pediatric disease such as neonatal liver failure in the case of TFAM ( 61 ) or fatal infantile hypertrophic cardiomyopathy in the case of AARS2 ( 62 ).…”

Section: Discussionmentioning

confidence: 99%

Premature Ovarian Insufficiency in CLPB Deficiency: Transcriptomic, Proteomic and Phenotypic Insights

Tucker

Baker

Hock

et al. 2022

The Journal of Clinical Endocrinology &Amp; Metabolism

Self Cite

View full text Add to dashboard Cite

Context Premature ovarian insufficiency (POI) is a common form of female infertility that most often presents as an isolated condition but can be part of various genetic syndromes. Early diagnosis and treatment of POI can minimise co-morbidity and improve health outcomes. Objective To determine the genetic cause of premature ovarian insufficiency (POI), intellectual disability, neutropenia and cataracts. Methods We performed whole exome sequencing (WES) followed by functional validation via RT-PCR, RNAseq and quantitative proteomics, as well as clinical update of previously reported patients with variants in the CaseinoLytic Peptidase B (CLPB) gene. Results We identified causative variants in CLPB, encoding a mitochondrial disaggregase. Variants in this gene are known to cause an autosomal recessive syndrome involving 3-methylglutaconic aciduria, neurological dysfunction, cataracts and neutropenia that is often fatal in childhood, however, there is likely a reporting bias towards severe cases. Using RNAseq and quantitative proteomics we validated causation and gained insight into genotype:phenotype correlation. Clinical follow-up of patients with CLPB deficiency who survived to adulthood identified POI and infertility as a common post-pubertal ailment. Conclusions A novel splicing variant is associated with CLPB deficiency in an individual who survived to adulthood. POI is a common feature of post-pubertal females with CLPB deficiency. Patients with CLPB deficiency should be referred to paediatric gynaecologists/endocrinologists for prompt POI diagnosis and hormone replacement therapy to minimise associated co-morbidities.

show abstract

A recessive variant in TFAM causes mtDNA depletion associated with primary ovarian insufficiency, seizures, intellectual disability and hearing loss

Cited by 17 publications

References 51 publications

A Method for In Situ Reverse Genetic Analysis of Proteins Involved mtDNA Replication

A Method for In Situ Reverse Genetic Analysis of Proteins Involved mtDNA Replication

A novel SETD2 variant causing global development delay without overgrowth in a Chinese 3-year-old boy

Premature Ovarian Insufficiency in CLPB Deficiency: Transcriptomic, Proteomic and Phenotypic Insights

Contact Info

Product

Resources

About