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A nonsense mutation of human XRCC4 is associated with adult-onset progressive encephalocardiomyopathy.

Bee L, Nasca A, Zanolini A, Cendron F, d'Adamo P, Costa R, Lamperti C, Celotti L, Ghezzi D, Zeviani M - EMBO Mol Med (2015)

Bottom Line: XRCC4 transcript levels were profoundly reduced, and the protein was undetectable in patients' skin fibroblasts.Gamma-irradiated mutant cells demonstrated reduction, but not abolition, of DSB repair.Surprisingly, neither immunodeficiency nor predisposition to malignancy was reported in these patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, University of Padua, Padua, Italy.

No MeSH data available.


Related in: MedlinePlus

Genetic and molecular features of XRCC4-mutant patientsPedigree. Black symbols designate affected subjects.Schematic view of wild-type and mutant (R225*) XRCC4 proteins with their main domains and phosphorylation sites. The numbering refers to amino acids of refseq: NP_071801.1. CTR: C-terminal region.Electropherograms of the XRCC4 genomic region encompassing the nucleotide substitutions in available members of the family.Quantitative real-time PCR of XRCC4 relative to GAPDH mRNA in affected (II-1 and II-2) and control (CT1 and CT2) fibroblasts. Each value refers to the mean of three independent experiments performed in duplicate. Error bars indicate the standard deviation.Immunoblot analysis of total lysates from fibroblasts (fbs) and of in vitro-synthesized proteins (i.v.p). fl: in vitro-translated full-length XRCC4 protein; ret.: reticulocyte lysate used for in vitro protein synthesis; 225*: in vitro-translated XRCC4 R225* truncated protein; Ct: lysate of control fbs; and II-1 and II-2: lysates of fbs from patient II-1 and II-2. α-XRCC4 (Abcam, 1:1,000) and α-GAPDH antibodies were used.Immunoblot analysis of total lysates from fibroblasts using α-LIG4 (GeneTex, 1:1,000) and α-SDHA antibodies. Ct: lysate of control fbs; II-1 and II-2: lysates of fbs from patient II-1 and II-2. The position of the molecular weight (MW) marker proteins is indicated.
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fig01: Genetic and molecular features of XRCC4-mutant patientsPedigree. Black symbols designate affected subjects.Schematic view of wild-type and mutant (R225*) XRCC4 proteins with their main domains and phosphorylation sites. The numbering refers to amino acids of refseq: NP_071801.1. CTR: C-terminal region.Electropherograms of the XRCC4 genomic region encompassing the nucleotide substitutions in available members of the family.Quantitative real-time PCR of XRCC4 relative to GAPDH mRNA in affected (II-1 and II-2) and control (CT1 and CT2) fibroblasts. Each value refers to the mean of three independent experiments performed in duplicate. Error bars indicate the standard deviation.Immunoblot analysis of total lysates from fibroblasts (fbs) and of in vitro-synthesized proteins (i.v.p). fl: in vitro-translated full-length XRCC4 protein; ret.: reticulocyte lysate used for in vitro protein synthesis; 225*: in vitro-translated XRCC4 R225* truncated protein; Ct: lysate of control fbs; and II-1 and II-2: lysates of fbs from patient II-1 and II-2. α-XRCC4 (Abcam, 1:1,000) and α-GAPDH antibodies were used.Immunoblot analysis of total lysates from fibroblasts using α-LIG4 (GeneTex, 1:1,000) and α-SDHA antibodies. Ct: lysate of control fbs; II-1 and II-2: lysates of fbs from patient II-1 and II-2. The position of the molecular weight (MW) marker proteins is indicated.

Mentions: We studied two 50-year-old twin brothers (II-1 and II-2), born to first-degree cousins. Their father, now in his seventies, is alive and well; their mother committed suicide at 55 years. No information is available on her psychiatric status before the event. A 47-year-old sister (II-3) is alive and well (pedigree in Fig1A).


A nonsense mutation of human XRCC4 is associated with adult-onset progressive encephalocardiomyopathy.

Bee L, Nasca A, Zanolini A, Cendron F, d'Adamo P, Costa R, Lamperti C, Celotti L, Ghezzi D, Zeviani M - EMBO Mol Med (2015)

Genetic and molecular features of XRCC4-mutant patientsPedigree. Black symbols designate affected subjects.Schematic view of wild-type and mutant (R225*) XRCC4 proteins with their main domains and phosphorylation sites. The numbering refers to amino acids of refseq: NP_071801.1. CTR: C-terminal region.Electropherograms of the XRCC4 genomic region encompassing the nucleotide substitutions in available members of the family.Quantitative real-time PCR of XRCC4 relative to GAPDH mRNA in affected (II-1 and II-2) and control (CT1 and CT2) fibroblasts. Each value refers to the mean of three independent experiments performed in duplicate. Error bars indicate the standard deviation.Immunoblot analysis of total lysates from fibroblasts (fbs) and of in vitro-synthesized proteins (i.v.p). fl: in vitro-translated full-length XRCC4 protein; ret.: reticulocyte lysate used for in vitro protein synthesis; 225*: in vitro-translated XRCC4 R225* truncated protein; Ct: lysate of control fbs; and II-1 and II-2: lysates of fbs from patient II-1 and II-2. α-XRCC4 (Abcam, 1:1,000) and α-GAPDH antibodies were used.Immunoblot analysis of total lysates from fibroblasts using α-LIG4 (GeneTex, 1:1,000) and α-SDHA antibodies. Ct: lysate of control fbs; II-1 and II-2: lysates of fbs from patient II-1 and II-2. The position of the molecular weight (MW) marker proteins is indicated.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4520657&req=5

fig01: Genetic and molecular features of XRCC4-mutant patientsPedigree. Black symbols designate affected subjects.Schematic view of wild-type and mutant (R225*) XRCC4 proteins with their main domains and phosphorylation sites. The numbering refers to amino acids of refseq: NP_071801.1. CTR: C-terminal region.Electropherograms of the XRCC4 genomic region encompassing the nucleotide substitutions in available members of the family.Quantitative real-time PCR of XRCC4 relative to GAPDH mRNA in affected (II-1 and II-2) and control (CT1 and CT2) fibroblasts. Each value refers to the mean of three independent experiments performed in duplicate. Error bars indicate the standard deviation.Immunoblot analysis of total lysates from fibroblasts (fbs) and of in vitro-synthesized proteins (i.v.p). fl: in vitro-translated full-length XRCC4 protein; ret.: reticulocyte lysate used for in vitro protein synthesis; 225*: in vitro-translated XRCC4 R225* truncated protein; Ct: lysate of control fbs; and II-1 and II-2: lysates of fbs from patient II-1 and II-2. α-XRCC4 (Abcam, 1:1,000) and α-GAPDH antibodies were used.Immunoblot analysis of total lysates from fibroblasts using α-LIG4 (GeneTex, 1:1,000) and α-SDHA antibodies. Ct: lysate of control fbs; II-1 and II-2: lysates of fbs from patient II-1 and II-2. The position of the molecular weight (MW) marker proteins is indicated.
Mentions: We studied two 50-year-old twin brothers (II-1 and II-2), born to first-degree cousins. Their father, now in his seventies, is alive and well; their mother committed suicide at 55 years. No information is available on her psychiatric status before the event. A 47-year-old sister (II-3) is alive and well (pedigree in Fig1A).

Bottom Line: XRCC4 transcript levels were profoundly reduced, and the protein was undetectable in patients' skin fibroblasts.Gamma-irradiated mutant cells demonstrated reduction, but not abolition, of DSB repair.Surprisingly, neither immunodeficiency nor predisposition to malignancy was reported in these patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, University of Padua, Padua, Italy.

No MeSH data available.


Related in: MedlinePlus