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1.
Geroscience ; 46(2): 1861-1879, 2024 Apr.
Article in English | MEDLINE | ID: mdl-37751047

ABSTRACT

Progeroid syndromes such as Hutchinson Gilford Progeroid syndrome (HGPS), Werner syndrome (WS) and Cockayne syndrome (CS), result in severely reduced lifespans and premature ageing. Normal senescent cells show splicing factor dysregulation, which has not yet been investigated in syndromic senescent cells. We sought to investigate the senescence characteristics and splicing factor expression profiles of progeroid dermal fibroblasts. Natural cellular senescence can be reversed by application of the senomorphic drug, trametinib, so we also investigated its ability to reverse senescence characteristics in syndromic cells. We found that progeroid cultures had a higher senescence burden, but did not always have differences in levels of proliferation, DNA damage repair and apoptosis. Splicing factor gene expression appeared dysregulated across the three syndromes. 10 µM trametinib reduced senescent cell load and affected other aspects of the senescence phenotype (including splicing factor expression) in HGPS and Cockayne syndromes. Werner syndrome cells did not demonstrate changes in in senescence following treatment. Splicing factor dysregulation in progeroid cells provides further evidence to support this mechanism as a hallmark of cellular ageing and highlights the use of progeroid syndrome cells in the research of ageing and age-related disease. This study suggests that senomorphic drugs such as trametinib could be a useful adjunct to therapy for progeroid diseases.


Subject(s)
Cockayne Syndrome , Progeria , Pyridones , Pyrimidinones , Werner Syndrome , Humans , Werner Syndrome/drug therapy , Werner Syndrome/genetics , Cockayne Syndrome/drug therapy , Cockayne Syndrome/genetics , Alternative Splicing/genetics , Senotherapeutics , Progeria/drug therapy , Progeria/genetics , RNA Splicing Factors
2.
Eur J Hum Genet ; 27(4): 574-581, 2019 04.
Article in English | MEDLINE | ID: mdl-30573803

ABSTRACT

Missense variants located to the "molecular brake" in the tyrosine kinase hinge region of platelet-derived growth factor receptor-ß, encoded by PFGFRB, can cause Penttinen-type (Val665Ala) and Penttinen-like (Asn666His) premature ageing syndromes, as well as infantile myofibromatosis (Asn666Lys and Pro660Thr). We have found the same de novo PDGFRB c.1997A>G p.(Asn666Ser) variants in two patients with lipodystrophy, acro-osteolysis and severely reduced vision due to corneal neovascularisation, reminiscent of a severe form of Penttinen syndrome with more pronounced connective tissue destruction. In line with this phenotype, patient skin fibroblasts were prone to apoptosis. Both in patient fibroblasts and stably transduced HeLa and HEK293 cells, autophosphorylation of PDGFRß was observed, as well as increased phosphorylation of downstream signalling proteins such as STAT1, PLCγ1, PTPN11/SHP2-Tyr580 and AKT. Phosphorylation of MAPK3 (ERK1) and PTPN11/SHP2-Tyr542 appeared unaffected. This suggests that this missense change not only weakens tyrosine kinase autoinhibition, but also influences substrate binding, as both PTPN11 tyrosines (Tyr542 and Tyr580) usually are phosphorylated upon PDGFR activation. Imatinib was a strong inhibitor of phosphorylation of all these targets, suggesting an option for precision medicine based treatment.


Subject(s)
Acro-Osteolysis/genetics , Cockayne Syndrome/genetics , Genetic Predisposition to Disease , Limb Deformities, Congenital/genetics , Progeria/genetics , Protein Tyrosine Phosphatase, Non-Receptor Type 11/genetics , Receptor, Platelet-Derived Growth Factor beta/genetics , Acro-Osteolysis/drug therapy , Acro-Osteolysis/physiopathology , Adult , Aging/genetics , Aging/pathology , Apoptosis/genetics , Cockayne Syndrome/drug therapy , Cockayne Syndrome/physiopathology , Female , HeLa Cells , Humans , Imatinib Mesylate/administration & dosage , Limb Deformities, Congenital/drug therapy , Limb Deformities, Congenital/physiopathology , Male , Mitogen-Activated Protein Kinase 3/genetics , Mutation, Missense/genetics , Myofibromatosis/congenital , Myofibromatosis/genetics , Myofibromatosis/physiopathology , Phenotype , Phosphorylation/genetics , Progeria/drug therapy , Progeria/physiopathology , Protein Interaction Maps/genetics , Protein-Tyrosine Kinases/genetics , Signal Transduction/genetics
4.
Proc Natl Acad Sci U S A ; 112(22): E2910-9, 2015 Jun 02.
Article in English | MEDLINE | ID: mdl-26038566

ABSTRACT

UV-sensitive syndrome (UV(S)S) and Cockayne syndrome (CS) are human disorders caused by CSA or CSB gene mutations; both conditions cause defective transcription-coupled repair and photosensitivity. Patients with CS also display neurological and developmental abnormalities and dramatic premature aging, and their cells are hypersensitive to oxidative stress. We report CSA/CSB-dependent depletion of the mitochondrial DNA polymerase-γ catalytic subunit (POLG1), due to HTRA3 serine protease accumulation in CS, but not in UV(s)S or control fibroblasts. Inhibition of serine proteases restored physiological POLG1 levels in either CS fibroblasts and in CSB-silenced cells. Moreover, patient-derived CS cells displayed greater nitroso-redox imbalance than UV(S)S cells. Scavengers of reactive oxygen species and peroxynitrite normalized HTRA3 and POLG1 levels in CS cells, and notably, increased mitochondrial oxidative phosphorylation, which was altered in CS cells. These data reveal critical deregulation of proteases potentially linked to progeroid phenotypes in CS, and our results suggest rescue strategies as a therapeutic option.


Subject(s)
Cockayne Syndrome/drug therapy , DNA Helicases/metabolism , DNA Repair Enzymes/metabolism , Mitochondrial Diseases/drug therapy , Progeria/pathology , Serine Proteinase Inhibitors/pharmacology , Blotting, Western , Cells, Cultured , Cockayne Syndrome/pathology , DNA Polymerase gamma , DNA, Mitochondrial/metabolism , DNA-Directed DNA Polymerase/metabolism , Fluorescent Antibody Technique , HeLa Cells , Humans , Mitochondrial Diseases/pathology , Peroxynitrous Acid/metabolism , Poly-ADP-Ribose Binding Proteins , Reactive Oxygen Species/metabolism , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Serine Proteinase Inhibitors/metabolism
5.
Clin Genet ; 87(1): 56-61, 2015.
Article in English | MEDLINE | ID: mdl-24354460

ABSTRACT

An extremely rare pellagra-like condition has been described, which was partially responsive to niacin and associated with a multisystem involvement. The condition was proposed to represent a novel autosomal recessive entity but the underlying mutation remained unknown for almost three decades. The objective of this study was to identify the causal mutation in the pellagra-like condition and investigate the mechanism by which niacin confers clinical benefit. Autozygosity mapping and exome sequencing were used to identify the causal mutation, and comet assay on patient fibroblasts before and after niacin treatment to assess its effect on DNA damage. We identified a single disease locus that harbors a novel mutation in ERCC5, thus confirming that the condition is in fact xeroderma pigmentosum/Cockayne syndrome (XP/CS) complex. Importantly, we also show that the previously described dermatological response to niacin is consistent with a dramatic protective effect against ultraviolet-induced DNA damage in patient fibroblasts conferred by niacin treatment. Our findings show the power of exome sequencing in reassigning previously described novel clinical entities, and suggest a mechanism for the dermatological response to niacin in patients with XP/CS complex. This raises interesting possibilities about the potential therapeutic use of niacin in XP.


Subject(s)
Cockayne Syndrome/drug therapy , Cockayne Syndrome/pathology , DNA-Binding Proteins/genetics , Endonucleases/genetics , Niacin/therapeutic use , Nuclear Proteins/genetics , Pellagra/pathology , Transcription Factors/genetics , Xeroderma Pigmentosum/drug therapy , Xeroderma Pigmentosum/pathology , Base Sequence , Child, Preschool , Cockayne Syndrome/genetics , Comet Assay , DNA Damage/drug effects , DNA Damage/radiation effects , Exome/genetics , Fatal Outcome , Female , Humans , Infant , Molecular Sequence Data , Niacin/pharmacology , Pedigree , Sequence Analysis, DNA , Xeroderma Pigmentosum/genetics
6.
Rev Invest Clin ; 62(5): 480-90, 2010.
Article in Spanish | MEDLINE | ID: mdl-21416736

ABSTRACT

Cockayne is a segmental progeroid syndrome that has autosomal recessive inheritance pattern. It is mainly characterized by Intrauterine growth retardation, severe postnatal growth deficiency, cachectic dwarfism, microcephaly, wizened face, sensorineural hearing loss, cataracts, dental caries, cardiac arrhythmias, hypertension, atherosclerosis, proteinuria, micropenis, renal failure, skeletal abnormalities, skin photosensitivity, decreased subcutaneous adipose tissue, cerebral atrophy, dementia, basal ganglia calcifications, ataxia and apraxia. It has a complex phenotype given by genetic heterogeneity. There are five gene responsible for this syndrome: CSA, CSB, XPB, XPD and XPG, in which various mutations have been found. The biochemical effect of these mutations includes dysfunctional protein of the repair system for oxidative damage to DNA, the complex coupled to transcription and the nucleotide excision repair system. Considering the role played for these proteins and its effects on clinical phenotype when they are deficient, we suggest that these genes might be candidates for analyzing susceptibility to common chronic degenerative diseases related to oxidative stress and aging.


Subject(s)
Cockayne Syndrome/genetics , DNA Damage , DNA Repair/genetics , Carbidopa/therapeutic use , Cockayne Syndrome/diagnosis , Cockayne Syndrome/drug therapy , Cockayne Syndrome/metabolism , Cockayne Syndrome/pathology , DNA Helicases/deficiency , DNA Helicases/genetics , DNA Helicases/physiology , DNA Repair Enzymes/deficiency , DNA Repair Enzymes/genetics , DNA Repair Enzymes/physiology , DNA-Binding Proteins/deficiency , DNA-Binding Proteins/genetics , DNA-Binding Proteins/physiology , Diagnosis, Differential , Endonucleases/deficiency , Endonucleases/genetics , Endonucleases/physiology , Genes, Recessive , Genetic Predisposition to Disease , Genotype , Growth Disorders/diagnosis , Humans , Levodopa/therapeutic use , Mutation , Nuclear Proteins/deficiency , Nuclear Proteins/genetics , Nuclear Proteins/physiology , Oxidative Stress/genetics , Phenotype , Photosensitivity Disorders/diagnosis , Poly-ADP-Ribose Binding Proteins , Transcription Factors/deficiency , Transcription Factors/genetics , Transcription Factors/physiology , Xeroderma Pigmentosum Group D Protein/deficiency , Xeroderma Pigmentosum Group D Protein/genetics , Xeroderma Pigmentosum Group D Protein/physiology
7.
Arch Neurol ; 65(8): 1117-21, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18695064

ABSTRACT

BACKGROUND: Gait difficulties, tremors, and coordination difficulties are common features of Cockayne syndrome that are consequences of leukodystrophy, cerebellar atrophy, and demyelinating neuropathy, but no pharmacotherapy for these disabling symptoms is available. OBJECTIVE: To determine whether carbidopa-levodopa relieves tremors and other motor complications of Cockayne syndrome. DESIGN: Mutation analysis and case report study. SETTING: Hospital clinic and genetics research laboratory. Patients We studied 3 patients with Cockayne syndrome, a rare autosomal recessive neurodegenerative disorder for which no known treatments are available. Intervention Carbidopa-levodopa therapy. MAIN OUTCOME MEASURES: Status of tremors, ability to perform daily tasks, serial physical examinations, and results of handwriting samples. RESULTS: All 3 patients had a clear reduction in tremors and improvements in handwriting and manipulation of utensils and cups. CONCLUSIONS: Patients with Cockayne syndrome should be evaluated carefully for movement disorders. A clinical trial should be considered to evaluate this therapy further.


Subject(s)
Carbidopa/administration & dosage , Cockayne Syndrome/drug therapy , Levodopa/administration & dosage , Movement Disorders/drug therapy , Adolescent , Cockayne Syndrome/complications , Cockayne Syndrome/genetics , Drug Therapy, Combination , Female , Humans , Male , Movement Disorders/complications , Movement Disorders/genetics
8.
Mech Ageing Dev ; 129(7-8): 492-7, 2008.
Article in English | MEDLINE | ID: mdl-18336867

ABSTRACT

Cancer, aging, and neurodegeneration are all associated with DNA damage and repair in complex fashions. Aging appears to be a cell and tissue-wide process linked to the insulin-dependent pathway in several DNA repair deficient disorders, especially in mice. Cancer and neurodegeneration appear to have complementary relationships to DNA damage and repair. Cancer arises from surviving cells, or even stem cells, that have down-regulated many pathways, including apoptosis, that regulate genomic stability in a multi-step process. Neurodegeneration however occurs in nondividing neurons in which the persistence of apoptosis in response to reactive oxygen species is, itself, pathological. Questions that remain open concern: sources and chemical nature of naturally occurring DNA damaging agents, especially whether mitochondria are the true source; the target tissues for DNA damage and repair; do the human DNA repair deficient diseases delineate specific pathways of DNA damage relevant to clinical outcomes; if naturally occurring reactive oxygen species are pathological in human repair deficient disease, would anti-oxidants or anti-apoptotic agents be feasible therapeutic agent?


Subject(s)
Aging/genetics , Cockayne Syndrome/genetics , DNA Damage , Neoplasms/genetics , Neurodegenerative Diseases/genetics , Xeroderma Pigmentosum/genetics , Animals , Cockayne Syndrome/diagnosis , Cockayne Syndrome/drug therapy , DNA Repair , Humans , Mice , Xeroderma Pigmentosum/diagnosis , Xeroderma Pigmentosum/drug therapy
9.
Pathol Int ; 56(11): 678-82, 2006 Nov.
Article in English | MEDLINE | ID: mdl-17040291

ABSTRACT

A 12-year-old girl, who had been diagnosed as having Cockayne syndrome (CS), was admitted for emaciation and dehydration. On admission the patient had mild chronic renal failure (glomerular filtration rate: GFR 50 mL/min) and hyperuricemia. After rehydration, allopurinol was commenced for her hyperuricemia. Then, her renal function rapidly deteriorated (GFR 20 mL/min) with enhancement of proximal tubular dysfunction and hypertension. A renal biopsy showed that the patient had acute tubulointerstitial nephritis (ATIN). Based on this diagnosis, allopurinol was stopped and prednisolone was started (2 mg/kg per day), following which the renal tubular function improved. However, the proteinuria intensified to become nephrotic syndrome. After 1 month the patient developed a gastric ulcer. Famotidine was commenced but GFR deteriorated and renal proximal tubular dysfunction re-occurred. The renal pathology was evaluated by referring to the previous reports of renal pathology in CS. It is suggested that rapid deterioration of the renal function in CS patients might be the result of ATIN. In addition, the present nephrotic syndrome seemed to be accompanied by ATIN, as in other reports.


Subject(s)
Acute Kidney Injury/etiology , Cockayne Syndrome/complications , Nephritis, Interstitial/etiology , Nephrotic Syndrome/etiology , Acute Disease , Acute Kidney Injury/drug therapy , Acute Kidney Injury/pathology , Allopurinol/therapeutic use , Child , Cockayne Syndrome/drug therapy , Cockayne Syndrome/pathology , Fatal Outcome , Female , Humans , Kidney Glomerulus/ultrastructure , Microscopy, Electron, Transmission , Nephritis, Interstitial/drug therapy , Nephritis, Interstitial/pathology , Nephrotic Syndrome/drug therapy , Nephrotic Syndrome/pathology , Prednisolone/therapeutic use , Recurrence
10.
Adv Exp Med Biol ; 431: 681-6, 1998.
Article in English | MEDLINE | ID: mdl-9598152

ABSTRACT

Validity of measurement of somatic cell mutation frequency (Mf) at the hprt locus for evaluating cancer risk of the given individual was determined in pediatric patients. Peripheral lymphocytes (PL) from patients with various diseases, including acute lymphoblastic leukemia (ALL) and Hodgkin's disease (HD), DNA repair deficient syndromes or short stature receiving growth hormone (GH), were isolated through Ficoll-Hypaque sedimentation with informed consent. Mf at the hprt locus of PL was determined by limiting dilution assay using 6-thioguanine (6-TG). Results were as follows. (1) ALL patients after chemotherapy had higher Mf than that of age-matched controls. (2) Patients with HD tended to have higher Mf after chemotherapy. (3) Among DNA-repair deficient syndromes, diseases which are susceptible to cancer (Xeroderma pigmentosum, Ataxia telangiectasia) have high Mf, but those without any cancer disposition (Cockayne syndrome, Rothmund-Thomson syndrome) have normal Mf. (4) GH-receiving patients have normal Mf, regardless of total doses of GH. Measurement of Mf at HPRT locus may be useful for evaluating cancer risk of pediatric patients.


Subject(s)
DNA Repair , Hodgkin Disease/drug therapy , Human Growth Hormone/adverse effects , Hypoxanthine Phosphoribosyltransferase/genetics , Lymphocytes/enzymology , Mutation , Neoplasms, Second Primary/epidemiology , Neoplasms/epidemiology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Adolescent , Adult , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Child , Child, Preschool , Cockayne Syndrome/drug therapy , DNA Damage , Hodgkin Disease/blood , Hodgkin Disease/enzymology , Humans , Infant , Neoplasms/chemically induced , Neoplasms, Second Primary/chemically induced , Precursor Cell Lymphoblastic Leukemia-Lymphoma/blood , Precursor Cell Lymphoblastic Leukemia-Lymphoma/enzymology , Risk Factors , Xeroderma Pigmentosum/drug therapy
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