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  1. AU="Semcesen, Liana N"
  2. AU="Beah, Peter Y"
  3. AU="Zakzuk, Josefina"
  4. AU="Buchner, Denise"
  5. AU="Xueting Feng"
  6. AU="Chen, Si-Rui"
  7. AU="Hoffmann, Sven"
  8. AU="Kang, Kyung Jun"
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  1. Article ; Online: Oligonucleotide correction of an intronic TIMMDC1 variant in cells of patients with severe neurodegenerative disorder.

    Kumar, Raman / Corbett, Mark A / Smith, Nicholas J C / Hock, Daniella H / Kikhtyak, Zoya / Semcesen, Liana N / Morimoto, Atsushi / Lee, Sangmoon / Stroud, David A / Gleeson, Joseph G / Haan, Eric A / Gecz, Jozef

    NPJ genomic medicine

    2022  Volume 7, Issue 1, Page(s) 9

    Abstract: TIMMDC1 encodes the Translocase of Inner Mitochondrial Membrane Domain-Containing protein 1 (TIMMDC1) subunit of complex I of the electron transport chain responsible for ATP production. We studied a consanguineous family with two affected children, now ... ...

    Abstract TIMMDC1 encodes the Translocase of Inner Mitochondrial Membrane Domain-Containing protein 1 (TIMMDC1) subunit of complex I of the electron transport chain responsible for ATP production. We studied a consanguineous family with two affected children, now deceased, who presented with failure to thrive in the early postnatal period, poor feeding, hypotonia, peripheral neuropathy and drug-resistant epilepsy. Genome sequencing data revealed a known, deep intronic pathogenic variant TIMMDC1 c.597-1340A>G, also present in gnomAD (~1/5000 frequency), that enhances aberrant splicing. Using RNA and protein analysis we show almost complete loss of TIMMDC1 protein and compromised mitochondrial complex I function. We have designed and applied two different splice-switching antisense oligonucleotides (SSO) to restore normal TIMMDC1 mRNA processing and protein levels in patients' cells. Quantitative proteomics and real-time metabolic analysis of mitochondrial function on patient fibroblasts treated with SSOs showed restoration of complex I subunit abundance and function. SSO-mediated therapy of this inevitably fatal TIMMDC1 neurologic disorder is an attractive possibility.
    Language English
    Publishing date 2022-01-28
    Publishing country England
    Document type Journal Article
    ZDB-ID 2813848-X
    ISSN 2056-7944 ; 2056-7944
    ISSN (online) 2056-7944
    ISSN 2056-7944
    DOI 10.1038/s41525-021-00277-7
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Severe NAD(P)HX Dehydratase (NAXD) Neurometabolic Syndrome May Present in Adulthood after Mild Head Trauma.

    Van Bergen, Nicole J / Gunanayagam, Karen / Bournazos, Adam M / Walvekar, Adhish S / Warmoes, Marc O / Semcesen, Liana N / Lunke, Sebastian / Bommireddipalli, Shobhana / Sikora, Tim / Patraskaki, Myrto / Jones, Dean L / Garza, Denisse / Sebire, Dale / Gooley, Samuel / McLean, Catriona A / Naidoo, Parm / Rajasekaran, Mugil / Stroud, David A / Linster, Carole L /
    Wallis, Mathew / Cooper, Sandra T / Christodoulou, John

    International journal of molecular sciences

    2023  Volume 24, Issue 4

    Abstract: We have previously reported that pathogenic variants in a key metabolite repair enzyme NAXD cause a lethal neurodegenerative condition triggered by episodes of fever in young children. However, the clinical and genetic spectrum of NAXD deficiency is ... ...

    Abstract We have previously reported that pathogenic variants in a key metabolite repair enzyme NAXD cause a lethal neurodegenerative condition triggered by episodes of fever in young children. However, the clinical and genetic spectrum of NAXD deficiency is broadening as our understanding of the disease expands and as more cases are identified. Here, we report the oldest known individual succumbing to NAXD-related neurometabolic crisis, at 32 years of age. The clinical deterioration and demise of this individual were likely triggered by mild head trauma. This patient had a novel homozygous
    MeSH term(s) Adult ; Child ; Child, Preschool ; Humans ; Hydro-Lyases/metabolism ; Mitochondria/metabolism ; NAD/metabolism ; Neurodegenerative Diseases/genetics ; Neurodegenerative Diseases/metabolism ; Proteomics ; Brain Concussion/complications ; Brain Concussion/genetics ; Brain Diseases, Metabolic/etiology ; Brain Diseases, Metabolic/genetics
    Chemical Substances Hydro-Lyases (EC 4.2.1.-) ; NAD (0U46U6E8UK) ; NAXD protein, human (EC 4.2.1.93)
    Language English
    Publishing date 2023-02-10
    Publishing country Switzerland
    Document type Case Reports
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms24043582
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Integrated multi-omics for rapid rare disease diagnosis on a national scale.

    Lunke, Sebastian / Bouffler, Sophie E / Patel, Chirag V / Sandaradura, Sarah A / Wilson, Meredith / Pinner, Jason / Hunter, Matthew F / Barnett, Christopher P / Wallis, Mathew / Kamien, Benjamin / Tan, Tiong Y / Freckmann, Mary-Louise / Chong, Belinda / Phelan, Dean / Francis, David / Kassahn, Karin S / Ha, Thuong / Gao, Song / Arts, Peer /
    Jackson, Matilda R / Scott, Hamish S / Eggers, Stefanie / Rowley, Simone / Boggs, Kirsten / Rakonjac, Ana / Brett, Gemma R / de Silva, Michelle G / Springer, Amanda / Ward, Michelle / Stallard, Kirsty / Simons, Cas / Conway, Thomas / Halman, Andreas / Van Bergen, Nicole J / Sikora, Tim / Semcesen, Liana N / Stroud, David A / Compton, Alison G / Thorburn, David R / Bell, Katrina M / Sadedin, Simon / North, Kathryn N / Christodoulou, John / Stark, Zornitza

    Nature medicine

    2023  Volume 29, Issue 7, Page(s) 1681–1691

    Abstract: Critically ill infants and children with rare diseases need equitable access to rapid and accurate diagnosis to direct clinical management. Over 2 years, the Acute Care Genomics program provided whole-genome sequencing to 290 families whose critically ... ...

    Abstract Critically ill infants and children with rare diseases need equitable access to rapid and accurate diagnosis to direct clinical management. Over 2 years, the Acute Care Genomics program provided whole-genome sequencing to 290 families whose critically ill infants and children were admitted to hospitals throughout Australia with suspected genetic conditions. The average time to result was 2.9 d and diagnostic yield was 47%. We performed additional bioinformatic analyses and transcriptome sequencing in all patients who remained undiagnosed. Long-read sequencing and functional assays, ranging from clinically accredited enzyme analysis to bespoke quantitative proteomics, were deployed in selected cases. This resulted in an additional 19 diagnoses and an overall diagnostic yield of 54%. Diagnostic variants ranged from structural chromosomal abnormalities through to an intronic retrotransposon, disrupting splicing. Critical care management changed in 120 diagnosed patients (77%). This included major impacts, such as informing precision treatments, surgical and transplant decisions and palliation, in 94 patients (60%). Our results provide preliminary evidence of the clinical utility of integrating multi-omic approaches into mainstream diagnostic practice to fully realize the potential of rare disease genomic testing in a timely manner.
    MeSH term(s) Infant ; Child ; Humans ; Rare Diseases/diagnosis ; Rare Diseases/genetics ; Rare Diseases/therapy ; Critical Illness ; Multiomics ; Whole Genome Sequencing/methods ; Exome Sequencing
    Language English
    Publishing date 2023-06-08
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1220066-9
    ISSN 1546-170X ; 1078-8956
    ISSN (online) 1546-170X
    ISSN 1078-8956
    DOI 10.1038/s41591-023-02401-9
    Database MEDical Literature Analysis and Retrieval System OnLINE

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