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The first nuclear-encoded complex I mutation in a patient with Leigh syndrome.

ABSTRACT: Nicotinamide adenine dinucleotide (NADH):ubiquinone oxidoreductase (complex I) is the largest multiprotein enzyme complex of the respiratory chain. The nuclear-encoded NDUFS8 (TYKY) subunit of complex I is highly conserved among eukaryotes and prokaryotes and contains two 4Fe4S ferredoxin consensus patterns, which have long been thought to provide the binding site for the iron-sulfur cluster N-2. The NDUFS8 cDNA contains an open reading frame of 633 bp, coding for 210 amino acids. Cycle sequencing of amplified NDUFS8 cDNA of 20 patients with isolated enzymatic complex I deficiency revealed two compound heterozygous transitions in a patient with neuropathologically proven Leigh syndrome. The first mutation was a C236T (P79L), and the second mutation was a G305A (R102H). Both mutations were absent in 70 control alleles and cosegregated within the family. A progressive clinical phenotype proceeding to death in the first months of life was expressed in the patient. In the 19 other patients with enzymatic complex I deficiency, no mutations were found in the NDUFS8 cDNA. This article describes the first molecular genetic link between a nuclear-encoded subunit of complex I and Leigh syndrome.

SUBMITTER: Loeffen J

PROVIDER: S-EPMC1377631 | biostudies-other | 1998 Dec

REPOSITORIES: biostudies-other

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The first nuclear-encoded complex I mutation in a patient with Leigh syndrome.

Loeffen J J Smeitink J J Triepels R R Smeets R R Schuelke M M Sengers R R Trijbels F F Hamel B B Mullaart R R van den Heuvel L L

American journal of human genetics 19981201 6

Nicotinamide adenine dinucleotide (NADH):ubiquinone oxidoreductase (complex I) is the largest multiprotein enzyme complex of the respiratory chain. The nuclear-encoded NDUFS8 (TYKY) subunit of complex I is highly conserved among eukaryotes and prokaryotes and contains two 4Fe4S ferredoxin consensus patterns, which have long been thought to provide the binding site for the iron-sulfur cluster N-2. The NDUFS8 cDNA contains an open reading frame of 633 bp, coding for 210 amino acids. Cycle sequenci ...[more]

PMID: 9837812

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Project description:BackgroundLeigh Syndrome (LS) is a rare genetic neurometabolic disorder, that leads to the degeneration of the central nervous system and subsequently, early death. LS can be caused by over 80 mutations in mitochondrial or nuclear DNA. Patient registries are important for many reasons, such as studying the natural history of the disease, improving the quality of care, and understanding the healthcare burden. For rare diseases, patient registries are significantly important as patient numbers are small, and funding is limited. Cure Mito Foundation started a global patient registry for LS in September 2021 to identify and learn about the LS patient population, facilitate clinical trial recruitment, and unite international patients and researchers. Priorities were to allow researchers and industry partners to access data at no cost through a clear and transparent process, active patient engagement, and sharing of results back to the community.ResultsPatient registry platform, survey design, data analysis process, and patient recruitment strategies are described. Reported results include demographics, diagnostic information, symptom history, loss of milestones, disease management, healthcare utilization, quality of life, and caregiver burden for 116 participants. Results show a high disease burden, but a relatively short time to diagnosis. Despite the challenges faced by families impacted by Leigh syndrome, participants, in general, are described as having a good quality of life and caregivers are overall resilient, while also reporting a significant amount of stress.ConclusionThis registry provides a straightforward, no-cost mechanism for data sharing and contacting patients for clinical trials or research participation, which is important given the recruitment challenges for clinical trials for rare diseases. This is the first publication to present results from a global patient registry for Leigh Syndrome, with details on a variety of patient-specific and caregiver outcomes reported for the first time. Additionally, this registry is the first for any mitochondrial disease with nearly 70% of participants residing outside of the United States. Future efforts include continued publication of results and further collaboration with patients, industry partners, and researchers.

Dataset Information

The first nuclear-encoded complex I mutation in a patient with Leigh syndrome.

Publications

The first nuclear-encoded complex I mutation in a patient with Leigh syndrome.

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