Homozygous mutation of MTPAP causes cellular radiosensitivity and persistent DNA double-strand breaks

Martin, Nathan; Nakamura, Kotoka; Paila, Uma Devi; Woo, Jennifer M.P.; Brown, Christina; Wright, James R.; Teraoka, Sharon N.; Haghayegh, Sara; McCurdy, Deborah; Schneider, Mark; Hu, Hailiang; Quinlan, Aaron R.; Gatti, Richard A.; Concannon, Patrick

doi:10.1038/cddis.2014.99

Cited by 15 publications

(17 citation statements)

References 58 publications

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“…Genome/functional analysis of Star‐PAP and PIPKIα depleted cells indicated that mRNAs encoding anti‐invasive factors, such as CDH1, CDH13, FEZ1, KISS1R, NME1, WIF1, are also targets of this polyadenylation activity (Laishram & Anderson, ). Outside of nuclear regulation, mitochondrial mRNA poly(A) polymerase (mtPAP) was observed to be associated with increased radiosensitivity, concurrent with increased reactive oxygen species (ROS) and DSBs (Martin et al, ).…”

Section: Cleavage and Polyadenylationmentioning

confidence: 99%

Connections between 3′ end processing and DNA damage response: Ten years later

Murphy

Kleiman

2019

WIREs RNA

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Ten years ago we reviewed how the cellular DNA damage response (DDR) is controlled by changes in the functional and structural properties of nuclear proteins, resulting in a timely coordinated control of gene expression that allows DNA repair. Expression of genes that play a role in DDR is regulated not only at transcriptional level during mRNA biosynthesis but also by changing steady‐state levels due to turnover of the transcripts. The 3′ end processing machinery, which is important in the regulation of mRNA stability, is involved in these gene‐specific responses to DNA damage. Here, we review the latest mechanistic connections described between 3′ end processing and DDR, with a special emphasis on alternative polyadenylation, microRNA and RNA binding proteins‐mediated deadenylation, and discuss the implications of deregulation of these steps in DDR and human disease. This article is categorized under: RNA Processing > 3′ End Processing RNA‐Based Catalysis > Miscellaneous RNA‐Catalyzed Reactions RNA in Disease and Development > RNA in Disease

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Section: Cleavage and Polyadenylationmentioning

confidence: 99%

Connections between 3′ end processing and DNA damage response: Ten years later

Murphy

Kleiman

2019

WIREs RNA

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“…Autosomal recessive inheritance of a p.Asn478Asp missense MTPAP variant has previously been reported in only eight patients, all of whom were homozygous for the same Old Amish founder mutation. 1,4 Here, we describe three novel MTPAP missense variants in a further three individuals from two unrelated families, inherited either in the compound heterozygous or homozygous state, and provide evidence that these variants affect mitochondrial transcript polyadenylation and subsequent expression of mitochondrially encoded proteins. Beyond the functional data that we provide, evidence in favor of pathogenicity derives from the rarity of all three variants (unrecorded on gnomAD), biallelic inheritance, appropriate segregation in the two siblings from F664, CADD scores above 25, the results of in silico analyses, and the congruence in clinical and radiological features across all three affected children.…”

Section: Discussionmentioning

confidence: 93%

“…18 Additionally, analysis of fibroblasts from P1 and P2 did not recapitulate a cellular phenotype of increased DNA damage, reduced DNA repair kinetics, and increased cell death following exposure to ionizing radiation recorded in two patients with the homozygous p.Asn478Asp MTPAP mutation. 4 The reason for this is unclear but might perhaps relate to the use of different cell types.…”

Section: Discussionmentioning

confidence: 99%

“…intellectual disability. 1,4 No neuroimaging data was reported for any of these individuals. The patients presented here exhibited a highly stereotyped clinical-radiological picture, characterized by a perinatal severe encephalopathy associated with neuroimaging somewhat reminiscent of congenital infection, profound developmental delay, and death before the age of 1 year.…”

Section: Discussionmentioning

confidence: 99%

“…1,3 A distinct cellular phenotype, characterized by increased DNA damage, reduced DNA repair kinetics, and increased cell death following exposure to ionizing radiation, was described in two further individuals of Amish descent carrying the same homozygous MTPAP mutation, in the absence of features of clinical radiosensitivity. 4 Here, we report three patients exhibiting an early-onset, lethal encephalopathy in association with biallelic rare missense variants in MTPAP, functional evidence of reduced polyadenylation of mitochondrial transcripts, and altered expression of mitochondrial proteins in fibroblasts. These findings likely expand the disease spectrum associated with mutations in MTPAP to include a lethal encephalopathy.…”

Section: Introductionmentioning

confidence: 86%

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Biallelic Mutations in MTPAP Associated with a Lethal Encephalopathy

et al. 2019

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Background A homozygous founder mutation in MTPAP/TENT6, encoding mitochondrial poly(A) polymerase (MTPAP), was first reported in six individuals of Old Order Amish descent demonstrating an early-onset, progressive spastic ataxia with optic atrophy and learning difficulties. MTPAP contributes to the regulation of mitochondrial gene expression through the polyadenylation of mitochondrially encoded mRNAs. Mitochondrial mRNAs with severely truncated poly(A) tails were observed in affected individuals, and mitochondrial protein expression was altered. Objective To determine the genetic basis of a perinatal encephalopathy associated with stereotyped neuroimaging and infantile death in three patients from two unrelated families. Methods Whole-exome sequencing was performed in two unrelated patients and the unaffected parents of one of these individuals. Variants and familial segregation were confirmed by Sanger sequencing. Polyadenylation of mitochondrial transcripts and de novo synthesis of mitochondrial proteins were assessed in patient's fibroblasts. Results Compound heterozygous p.Ile428Thr and p.Arg523Trp substitutions in MTPAP were recorded in two affected siblings from one family, and a homozygous p.Ile385Phe missense variant identified in a further affected child from a second sibship. Mitochondrial poly(A) tail analysis demonstrated shorter posttranscriptional additions to the mitochondrial transcripts, as well as an altered expression of mitochondrial proteins in the fibroblasts of the two siblings compared with healthy controls. Conclusion Mutations in MTPAP likely cause an autosomal recessive perinatal encephalopathy with lethality in the first year of life.

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Genes affecting ionizing radiation survival identified through combined exome sequencing and functional screening

et al. 2021

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The study of genetic syndromes characterized by sensitivity to DNA damaging agents has provided important insights into the mechanisms that maintain genome stability and identified novel targets for cancer therapies. Here, we used exome sequencing to study 51 unrelated individuals with previously reported hypersensitivity to ionizing radiation as well as a range of neurologic, immunologic, and developmental features, but who did not clearly fit any previously defined genetic syndrome. Based on the combination of variant identification, computational evidence of deleteriousness, and functional screening, we identified three groups of subjects. Two subjects carried the bi‐allelic loss of function variants in causative genes for known DNA damage response syndromes. Eight subjects carried the single loss of function variants in causative genes for DNA damage response syndromes, six of whom also carried predicted deleterious variants in other genes with DNA damage‐related functions. Three subjects carried deleterious mutations in genes without obvious roles in DNA damage responses. However, treatment of U2OS cells with small interfering RNA targeting these genes resulted in significantly increased radiation sensitivity. Our results suggest that gene–gene interaction may contribute to ionizing radiation sensitivity as well as highlighting possible roles for several genes not obviously involved in the response to DNA damage.

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Homozygous mutation of MTPAP causes cellular radiosensitivity and persistent DNA double-strand breaks

Cited by 15 publications

References 58 publications

Connections between 3′ end processing and DNA damage response: Ten years later

Connections between 3′ end processing and DNA damage response: Ten years later

Biallelic Mutations in MTPAP Associated with a Lethal Encephalopathy

Genes affecting ionizing radiation survival identified through combined exome sequencing and functional screening

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