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  • 1
    Language: English
    In: American journal of human genetics, 2014-12-04, Vol.95 (6), p.763-770
    Description: Catel-Manzke syndrome is characterized by Pierre Robin sequence and a unique form of bilateral hyperphalangy causing a clinodactyly of the index finger. We describe the identification of homozygous and compound heterozygous mutations in TGDS in seven unrelated individuals with typical Catel-Manzke syndrome by exome sequencing. Six different TGDS mutations were detected: c.892A〉G (p.Asn298Asp), c.270_271del (p.Lys91Asnfs∗22), c.298G〉T (p.Ala100Ser), c.294T〉G (p.Phe98Leu), c.269A〉G (p.Glu90Gly), and c.700T〉C (p.Tyr234His), all predicted to be disease causing. By using haplotype reconstruction we showed that the mutation c.298G〉T is probably a founder mutation. Due to the spectrum of the amino acid changes, we suggest that loss of function in TGDS is the underlying mechanism of Catel-Manzke syndrome. TGDS (dTDP-D-glucose 4,6-dehydrogenase) is a conserved protein belonging to the SDR family and probably plays a role in nucleotide sugar metabolism.
    Subject(s): Haplotypes ; Humans ; Middle Aged ; Child, Preschool ; Molecular Sequence Data ; Infant ; Male ; Young Adult ; Adult ; Female ; Pierre Robin Syndrome - enzymology ; Amino Acid Sequence ; Oxidoreductases - metabolism ; Oxidoreductases - genetics ; Models, Molecular ; Sequence Analysis, DNA ; Homozygote ; Exome - genetics ; Sequence Alignment ; Hand Deformities, Congenital - enzymology ; Pierre Robin Syndrome - genetics ; Hand Deformities, Congenital - genetics ; Pedigree ; Adolescent ; Heterozygote ; Mutation ; Causes of ; Genetic research ; Genetic disorders ; Research ; Gene mutations ; Index Medicus ; Report
    ISSN: 0002-9297
    E-ISSN: 1537-6605
    Source: PubMed Central
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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  • 2
    Language: English
    In: American journal of human genetics, 2017-11-02, Vol.101 (5), p.833-843
    Description: Gorlin-Chaudhry-Moss syndrome (GCMS) is a dysmorphic syndrome characterized by coronal craniosynostosis and severe midface hypoplasia, body and facial hypertrichosis, microphthalmia, short stature, and short distal phalanges. Variable lipoatrophy and cutis laxa are the basis for a progeroid appearance. Using exome and genome sequencing, we identified the recurrent de novo mutations c.650G〉A (p.Arg217His) and c.649C〉T (p.Arg217Cys) in SLC25A24 in five unrelated girls diagnosed with GCMS. Two of the girls had pronounced neonatal progeroid features and were initially diagnosed with Wiedemann-Rautenstrauch syndrome. SLC25A24 encodes a mitochondrial inner membrane ATP-Mg/Pi carrier. In fibroblasts from affected individuals, the mutated SLC25A24 showed normal stability. In contrast to control cells, the probands’ cells showed mitochondrial swelling, which was exacerbated upon treatment with hydrogen peroxide (H2O2). The same effect was observed after overexpression of the mutant cDNA. Under normal culture conditions, the mitochondrial membrane potential of the probands’ fibroblasts was intact, whereas ATP content in the mitochondrial matrix was lower than that in control cells. However, upon H2O2 exposure, the membrane potential was significantly elevated in cells harboring the mutated SLC25A24. No reduction of mitochondrial DNA copy number was observed. These findings demonstrate that mitochondrial dysfunction with increased sensitivity to oxidative stress is due to the SLC25A24 mutations. Our results suggest that the SLC25A24 mutations induce a gain of pathological function and link mitochondrial ATP-Mg/Pi transport to the development of skeletal and connective tissue.
    Subject(s): Gorlin-Chaudhry-Moss syndrome ; hypertrichosis ; craniosynostosis ; lipoatrophy ; cutis laxa ; mitochondrial swelling ; premature aging ; oxidative stress ; SLC25A24 ; Humans ; Child, Preschool ; Adenosine Triphosphate - genetics ; Fetal Growth Retardation - genetics ; Infant ; Mitochondrial Proteins - genetics ; Membrane Potential, Mitochondrial - drug effects ; DNA, Mitochondrial - genetics ; Mitochondria - genetics ; Antiporters - genetics ; Membrane Potential, Mitochondrial - genetics ; Female ; Child ; Abnormalities, Multiple - genetics ; Craniofacial Abnormalities - genetics ; Ductus Arteriosus, Patent - genetics ; Craniosynostoses - genetics ; Hydrogen Peroxide - pharmacology ; Oxidative Stress - genetics ; Cutis Laxa - genetics ; Mitochondria - drug effects ; Progeria - genetics ; Fibroblasts - pathology ; Mutation - genetics ; Exome - genetics ; Hypertrichosis - genetics ; Adolescent ; Calcium-Binding Proteins - genetics ; Index Medicus ; Oxidative stress ; Lipoatrophy ; Mitochondrial swelling ; Craniosynostosis ; Gorlin-chaudhry-moss syndrome ; Hypertrichosis ; Cutis laxa ; Premature aging ; Report
    ISSN: 0002-9297
    E-ISSN: 1537-6605
    Source: PubMed Central
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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  • 3
    Language: English
    In: ChemMedChem, 2008-12-15, Vol.3 (12), p.1893-1904
    Description: Rho kinase plays a pivotal role in several cellular processes such as vasoregulation, making it a suitable target for the treatment of hypertension and related disorders. We discovered a new compound class of Rho kinase (ROCK) inhibitors containing a 7‐azaindole hinge‐binding scaffold tethered to an aminopyrimidine core. Herein we describe the structure–activity relationships elucidated through biochemical and functional assays. The introduction of suitable substituents at the 3‐position of the bicyclic moiety led to an increase in activity, which was required to design compounds with favorable pharmacokinetic profile. Azaindole 32 was identified as a highly selective and orally available ROCK inhibitor able to cause a sustained blood pressure reduction in vivo. A new compound class of Rho kinase (ROCK) inhibitors containing a 7‐azaindole hinge‐binding moiety was discovered. The introduction of substituents at the 3‐position of the bicyclic ring system led to a significant increase in activity and permitted the design of compounds with a favorable pharmacokinetic profile. The ROCK inhibitors are orally bioavailable and mediate a sustained blood pressure lowering effect in vivo.
    Subject(s): inhibitors ; 7‐azaindole ; Rho kinase ; structure–activity relationships ; vasorelaxation ; Rats, Wistar ; Pyrimidines - chemical synthesis ; Enzyme Inhibitors - pharmacology ; Indoles - chemical synthesis ; Models, Molecular ; Rats ; Structure-Activity Relationship ; Pyrimidines - pharmacology ; Enzyme Inhibitors - chemical synthesis ; Pyrimidines - chemistry ; rho-Associated Kinases - antagonists & inhibitors ; Animals ; Enzyme Inhibitors - chemistry ; Drug Design ; Inhibitory Concentration 50 ; Indoles - pharmacology ; Indoles - chemistry ; rho-Associated Kinases - pharmacology
    ISSN: 1860-7179
    E-ISSN: 1860-7187
    Source: Alma/SFX Local Collection
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  • 4
    Language: English
    In: ChemMedChem, 2008-12-15, Vol.3 (12), p.1797-1797
    ISSN: 1860-7179
    E-ISSN: 1860-7187
    Source: Alma/SFX Local Collection
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