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A uniparental isodisomy event introducing homozygous pathogenic variants drives a multisystem metabolic disorder. / Daniels, Eileen G.; Alders, Marielle; Lezzerini, Marco et al.

In: Cold Spring Harbor molecular case studies, Vol. 5, No. 6, a004457, 2019.

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@article{83adda19087e490ba0ffbdd77777b6f1,
title = "A uniparental isodisomy event introducing homozygous pathogenic variants drives a multisystem metabolic disorder",
abstract = "Uniparental isodisomy (UPiD) is a rare genetic event that occurs when two identical copies of a single chromosome are inherited fromone parent. Here we report a patient with a severe, multisystem metabolic disorder who inherited two copies of Chromosome 12 from her father. He was a heterozygous carrier of a variant in the muscle-specific enzyme 6-phosphofructokinase (PFKM) gene and of a truncating variant in the pseudouridine synthase 1 (PUS1) gene (both on Chromosome 12), resulting in a homozygous state of these mutations in his daughter. The PFKM gene functions in glycolysis and is linked to Tarui syndrome. The PUS1 gene functions in mitochondrial tRNA processing and is linked to myopathy, lactic acidosis, and sideroblastic anemia (MLASA). Analysis of human dermal fibroblasts, which do not express PFKM, revealed a loss of PUS1 mRNA and PUS1 protein only in the patient cells compared to healthy controls. The patient cells also revealed a reduction of the mitochondrial- encoded protein MTCO1, whereas levels of the nuclear-encoded SDHA remained unchanged, suggesting a specific impairment of mitochondrial translation. Further destabilization of these cells is suggested by the altered levels of BAX, BCL-2, and TP53 proteins, alterations that become augmented upon exposure of the cells toDNA damage. The results illustrate the efficacy of UPiD events to reveal rare pathogenic variants in human disease and demonstrate how these events can lead to cellular destabilization.",
author = "Daniels, {Eileen G.} and Marielle Alders and Marco Lezzerini and Andrew McDonald and Marjolein Peters and Kuijpers, {Taco W.} and Phillis Lakeman and Houtkooper, {Riekelt H.} and MacInnes, {Alyson W.}",
year = "2019",
doi = "10.1101/mcs.a004457",
language = "English",
volume = "5",
journal = "Cold Spring Harbor molecular case studies",
issn = "2373-2873",
publisher = "Cold Spring Harbor Laboratory Press",
number = "6",

}

RIS

TY - JOUR

T1 - A uniparental isodisomy event introducing homozygous pathogenic variants drives a multisystem metabolic disorder

AU - Daniels, Eileen G.

AU - Alders, Marielle

AU - Lezzerini, Marco

AU - McDonald, Andrew

AU - Peters, Marjolein

AU - Kuijpers, Taco W.

AU - Lakeman, Phillis

AU - Houtkooper, Riekelt H.

AU - MacInnes, Alyson W.

PY - 2019

Y1 - 2019

N2 - Uniparental isodisomy (UPiD) is a rare genetic event that occurs when two identical copies of a single chromosome are inherited fromone parent. Here we report a patient with a severe, multisystem metabolic disorder who inherited two copies of Chromosome 12 from her father. He was a heterozygous carrier of a variant in the muscle-specific enzyme 6-phosphofructokinase (PFKM) gene and of a truncating variant in the pseudouridine synthase 1 (PUS1) gene (both on Chromosome 12), resulting in a homozygous state of these mutations in his daughter. The PFKM gene functions in glycolysis and is linked to Tarui syndrome. The PUS1 gene functions in mitochondrial tRNA processing and is linked to myopathy, lactic acidosis, and sideroblastic anemia (MLASA). Analysis of human dermal fibroblasts, which do not express PFKM, revealed a loss of PUS1 mRNA and PUS1 protein only in the patient cells compared to healthy controls. The patient cells also revealed a reduction of the mitochondrial- encoded protein MTCO1, whereas levels of the nuclear-encoded SDHA remained unchanged, suggesting a specific impairment of mitochondrial translation. Further destabilization of these cells is suggested by the altered levels of BAX, BCL-2, and TP53 proteins, alterations that become augmented upon exposure of the cells toDNA damage. The results illustrate the efficacy of UPiD events to reveal rare pathogenic variants in human disease and demonstrate how these events can lead to cellular destabilization.

AB - Uniparental isodisomy (UPiD) is a rare genetic event that occurs when two identical copies of a single chromosome are inherited fromone parent. Here we report a patient with a severe, multisystem metabolic disorder who inherited two copies of Chromosome 12 from her father. He was a heterozygous carrier of a variant in the muscle-specific enzyme 6-phosphofructokinase (PFKM) gene and of a truncating variant in the pseudouridine synthase 1 (PUS1) gene (both on Chromosome 12), resulting in a homozygous state of these mutations in his daughter. The PFKM gene functions in glycolysis and is linked to Tarui syndrome. The PUS1 gene functions in mitochondrial tRNA processing and is linked to myopathy, lactic acidosis, and sideroblastic anemia (MLASA). Analysis of human dermal fibroblasts, which do not express PFKM, revealed a loss of PUS1 mRNA and PUS1 protein only in the patient cells compared to healthy controls. The patient cells also revealed a reduction of the mitochondrial- encoded protein MTCO1, whereas levels of the nuclear-encoded SDHA remained unchanged, suggesting a specific impairment of mitochondrial translation. Further destabilization of these cells is suggested by the altered levels of BAX, BCL-2, and TP53 proteins, alterations that become augmented upon exposure of the cells toDNA damage. The results illustrate the efficacy of UPiD events to reveal rare pathogenic variants in human disease and demonstrate how these events can lead to cellular destabilization.

UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85076501849&origin=inward

UR - https://www.ncbi.nlm.nih.gov/pubmed/31653659

U2 - 10.1101/mcs.a004457

DO - 10.1101/mcs.a004457

M3 - Article

C2 - 31653659

VL - 5

JO - Cold Spring Harbor molecular case studies

JF - Cold Spring Harbor molecular case studies

SN - 2373-2873

IS - 6

M1 - a004457

ER -

ID: 10424636