Biallelic variants inDAP3result in reduced assembly of the mitoribosomal small subunit with altered intrinsic and extrinsic apoptosis and a Perrault syndrome-spectrum phenotype

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 21, 2024

The mitoribosome synthesizes 13 protein subunits of the oxidative phosphorylation system encoded by mitochondrial genome. is composed 12S rRNA, 16S rRNA and 82 mitoribosomal proteins nuclear genes. To date, variants in 12 genes encoding are associated with rare monogenic disorders, frequently show combined deficiency. Here, we describe five unrelated individuals biallelic

Language: Английский

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Substantial role of rare inherited variation in individuals with developmental disorders

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 29, 2024

Abstract While the role of de novo and recessively-inherited coding variation in risk for rare developmental disorders (DDs) has been well established, contribution damaging dominantly-inherited from parents is less explored. Here, we investigated variants to DDs by analyzing 13,452 individuals with DDs, 18,613 their family members, 3,943 controls using a combination family-based case/control analyses. In line previous studies other neuropsychiatric traits, found significant burden (allele frequency < 1×10 -5 ) predicted loss-of-function (pLoF) missense variants, vast majority which are inherited apparently unaffected parents. These predominantly burdens strongest DD-associated genes or those intolerant pLoF general population, however estimate that ∼10% excess these DD cases within genes, implying many more loci yet be identified. We similar, but attenuated, when comparing controls, indicating have elevated due overtransmitted affected children. 6-8.5% population attributable population. Finally, apply Bayesian framework combine evidence analyses rare, mostly-inherited prior mutation highlight an additional 25 candidate DD- associated further follow up.

Language: Английский

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Bi-allelic variants in DAP3 result in reduced assembly of the mitoribosomal small subunit with altered apoptosis and a Perrault-syndrome-spectrum phenotype

The American Journal of Human Genetics, Journal Year: 2024, Volume and Issue: 112(1), P. 59 - 74

Published: Dec. 18, 2024

The mitochondrial ribosome (mitoribosome) synthesizes 13 protein subunits of the oxidative phosphorylation system encoded by genome. mitoribosome is composed 12S rRNA, 16S and 82 mitoribosomal proteins nuclear genes. To date, variants in 12 genes encoding are associated with rare monogenic disorders frequently show combined deficiency. Here, we describe five unrelated individuals bi-allelic death-associated 3 (DAP3), a gene small subunit 29 (MRPS29), variable clinical presentations ranging from Perrault syndrome (sensorineural hearing loss ovarian insufficiency) to an early childhood neurometabolic phenotype. Assessment respiratory-chain function proteomic profiling fibroblasts affected demonstrated reduced MRPS29 amounts and, consequently, decreased levels additional components subunit, as well deficiency complexes I IV. Lentiviral transduction wild-type DAP3 cDNA increased mRNA expression partially rescued MRPS7, MRPS9, complex IV subunits, demonstrating pathogenicity variants. Protein modeling suggested that disease-associated missense can impact ADP binding, vitro assays consequently reduce both intrinsic extrinsic apoptotic sensitivity, thermal stability, GTPase activity. Our study presents genetic functional evidence result multisystem disorder pleiotropic presentations, consistent dysfunction.

Language: Английский

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Dissecting the Reduced Penetrance of Putative Loss-of-Function Variants in Population-Scale Biobanks

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 24, 2024

Abstract Loss-of-function variants (LoFs) disrupt the activity of their impacted gene. They are often associated with clinical phenotypes, including autosomal dominant diseases driven by haploinsufficiency. Recent analyses using biobanks have suggested that LoF penetrance for some haploinsufficient disorders may be low, an observation has important implications population genomic screening. However, also rife missing data, and reliability these findings remains uncertain. Here, we examine putative LoFs (pLoFs) a cohort ≈24,000 carriers derived from two population-scale biobanks: UK Biobank All Us Research Program. We investigate several possible etiologies reduced pLoF penetrance, biobank recruitment biases, annotation artifacts, missed diagnoses, incomplete records. Systematically accounting factors increased but widespread remained. Therefore, hypothesized other must driving this phenomenon. To test this, trained machine learning models to identify pLoFs high features specific each variant. These were predictive across range types, those prior evidence pathogenicity. This suggests is in fact common, care should taken when counseling asymptomatic carriers.

Language: Английский

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HSP90 buffers deleterious genetic variations inBRCA1

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 17, 2024

Protein-folding chaperone HSP90 buffers genetic variation in diverse organisms, but the clinical significance of buffering disease remains unclear. Here, we show that mutations BRCT domain BRCA1. HSP90-buffered

Language: Английский

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