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De Novo Mutations in SLC25A24 Cause a Craniosynostosis Syndrome with Hypertrichosis, Progeroid Appearance, and Mitochondrial Dysfunction

Ehmke, Nadja ; Graul-Neumann, Luitgard ; Smorag, Lukasz ; [et al.]

2017

ISSN: 0002-9297

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Language: English

In: American journal of human genetics, 2017, 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): Abnormalities, Multiple - genetics ; Adenosine Triphosphate - genetics ; Adolescent ; Antiporters - genetics ; Calcium-Binding Proteins - genetics ; Child ; Child, Preschool ; Craniofacial Abnormalities - genetics ; Craniosynostoses - genetics ; Craniosynostosis ; Cutis laxa ; Cutis Laxa - genetics ; DNA, Mitochondrial - genetics ; Ductus Arteriosus, Patent - genetics ; Exome - genetics ; Female ; Fetal Growth Retardation - genetics ; Fibroblasts - pathology ; Gorlin-Chaudhry-Moss syndrome ; Humans ; Hydrogen Peroxide - pharmacology ; Hypertrichosis ; Hypertrichosis - genetics ; Infant ; Lipoatrophy ; Membrane Potential, Mitochondrial - drug effects ; Membrane Potential, Mitochondrial - genetics ; Mitochondria - drug effects ; Mitochondria - genetics ; Mitochondrial Proteins - genetics ; Mitochondrial swelling ; Mutation - genetics ; Oxidative stress ; Oxidative Stress - genetics ; Premature aging ; Progeria - genetics ; Report ; SLC25A24

ISSN: 0002-9297

E-ISSN: 1537-6605

DOI: 10.1016/j.ajhg.2017.09.016

Source: PubMed Central

URL: https://www.ncbi.nlm.nih.gov/pubmed/29100093$$D View this record in MEDLINE/PubMed

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Homozygous and Compound-Heterozygous Mutations in TGDS Cause Catel-Manzke Syndrome

Ehmke, Nadja ; Caliebe, Almuth ; Koenig, Rainer ; [et al.]

2014

ISSN: 0002-9297

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Language: English

In: American journal of human genetics, 2014, 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): Adolescent ; Adult ; Amino Acid Sequence ; Amino acids ; Causes of ; Child, Preschool ; Exome - genetics ; Female ; Gene mutations ; Genetic disorders ; Genetic research ; Hand Deformities, Congenital - enzymology ; Hand Deformities, Congenital - genetics ; Haplotypes ; Heterozygote ; Homozygote ; Humans ; Infant ; Male ; Metabolism ; Middle Aged ; Models, Molecular ; Molecular Sequence Data ; Mutation ; Oxidoreductases - genetics ; Oxidoreductases - metabolism ; Pedigree ; Pierre Robin Syndrome - enzymology ; Pierre Robin Syndrome - genetics ; Report ; Sequence Alignment ; Sequence Analysis, DNA ; Young Adult

ISSN: 0002-9297

E-ISSN: 1537-6605

DOI: 10.1016/j.ajhg.2014.11.004

Source: PubMed Central

URL: https://www.ncbi.nlm.nih.gov/pubmed/25480037$$D View this record in MEDLINE/PubMed

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CADA: phenotype-driven gene prioritization based on a case-enriched knowledge graph

Peng, Chengyao ; Dieck, Simon ; Schmid, Alexander ; [et al.]

2021

ISSN: 2631-9268

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Language: English

In: NAR genomics and bioinformatics, 2021, Vol.3 (3), p.lqab078-lqab078

Description: Abstract Many rare syndromes can be well described and delineated from other disorders by a combination of characteristic symptoms. These phenotypic features are best documented with terms of the Human Phenotype Ontology (HPO), which are increasingly used in electronic health records (EHRs), too. Many algorithms that perform HPO-based gene prioritization have also been developed; however, the performance of many such tools suffers from an over-representation of atypical cases in the medical literature. This is certainly the case if the algorithm cannot handle features that occur with reduced frequency in a disorder. With Cada, we built a knowledge graph based on both case annotations and disorder annotations. Using network representation learning, we achieve gene prioritization by link prediction. Our results suggest that Cada exhibits superior performance particularly for patients that present with the pathognomonic findings of a disease. Additionally, information about the frequency of occurrence of a feature can readily be incorporated, when available. Crucial in the design of our approach is the use of the growing amount of phenotype–genotype information that diagnostic labs deposit in databases such as ClinVar. By this means, Cada is an ideal reference tool for differential diagnostics in rare disorders that can also be updated regularly.

ISSN: 2631-9268

E-ISSN: 2631-9268

DOI: 10.1093/nargab/lqab078

Source: PubMed Central

Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery

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Design and Synthesis of Potent and Selective Azaindole-Based Rho Kinase (ROCK) Inhibitors

Schirok, Hartmut ; Kast, Raimund ; Figueroa-Pérez, Santiago ; [et al.]

2008

ISSN: 1860-7179

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Language: English

In: ChemMedChem, 2008, 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): 7-azaindole ; Animals ; Drug Design ; Enzyme Inhibitors - chemical synthesis ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacology ; Indoles - chemical synthesis ; Indoles - chemistry ; Indoles - pharmacology ; inhibitors ; Inhibitory Concentration 50 ; Models, Molecular ; Pyrimidines - chemical synthesis ; Pyrimidines - chemistry ; Pyrimidines - pharmacology ; Rats ; Rats, Wistar ; Rho kinase ; rho-Associated Kinases - antagonists & inhibitors ; rho-Associated Kinases - pharmacology ; Structure-Activity Relationship ; structure-activity relationships ; vasorelaxation

ISSN: 1860-7179

E-ISSN: 1860-7187

DOI: 10.1002/cmdc.200800211

Source: Get It Now

Source: Wiley-Blackwell Full Collection 2014

URL: https://www.ncbi.nlm.nih.gov/pubmed/18973168$$D View this record in MEDLINE/PubMed

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Cover Picture: Design and Synthesis of Potent and Selective Azaindole-Based Rho Kinase (ROCK) Inhibitors (ChemMedChem 12/2008)

Schirok, Hartmut ; Kast, Raimund ; Figueroa-Pérez, Santiago ; [et al.]

2008

ISSN: 1860-7179

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Language: English

In: ChemMedChem, 2008, Vol.3 (12), p.1797-1797

Subject(s): 7-azaindole ; inhibitors ; Rho kinase ; structure-activity relationships ; vasorelaxation

ISSN: 1860-7179

E-ISSN: 1860-7187

DOI: 10.1002/cmdc.200890046

Source: Get It Now

Source: Wiley-Blackwell Full Collection 2014

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