Related Experiment Video

Updated: Dec 22, 2025

In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila
06:41

In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila

Published on: August 20, 2019

14.1K

A homozygous variant in NDUFA8 is associated with developmental delay, microcephaly, and epilepsy due to

Yukiko Yatsuka1,2, Yoshihito Kishita1,2, Luke E Formosa3

  • 1Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, Tokyo, Japan.

Clinical Genetics
|May 10, 2020
PubMed

Insights

Mitochondrial complex I deficiency can stem from NDUFA8 gene variants. This study identifies a novel NDUFA8 mutation causing severe mitochondrial disease, impacting neurological development.

Area of Science:

  • Biochemistry
  • Genetics
  • Neuroscience

Background:

  • Mitochondrial complex I deficiency is a significant cause of inherited metabolic disorders, often linked to genetic defects affecting enzyme structure and assembly.
  • Pathogenic variants in nuclear or mitochondrial genes can disrupt the intricate process of complex I biogenesis, leading to cellular dysfunction.

Observation:

  • A patient presented with developmental delay, microcephaly, and epilepsy, exhibiting biochemical defects in mitochondrial complex I.
  • Fibroblast analysis revealed reduced expression of NDUFA8 and other complex I subunits, indicating assembly defects.
  • Whole-exome sequencing identified a homozygous variant in the NDUFA8 gene in the affected patient.

Findings:

  • The identified NDUFA8 variant was confirmed to be pathogenic, causing severe defects in mitochondrial complex I assembly.
  • Restoration of NDUFA8 gene function in patient-derived cells normalized complex I activity and oxygen consumption.
  • Functional studies in knockout cells further validated the role of the NDUFA8 variant in impairing complex I biogenesis.

Implications:

  • This research establishes NDUFA8 as a novel gene associated with mitochondrial complex I deficiency and progressive neurological disorders.
  • The findings expand the genetic landscape of mitochondrial diseases, offering new diagnostic targets.
  • Understanding the role of NDUFA8 in complex I assembly provides insights into potential therapeutic strategies for related neurodevelopmental conditions.
Keywords:
CX9C motifOXPHOScomplex I deficiencydisulfide relay import pathwaymitochondrial diseasemitochondrial intermembrane space

More Related Videos

A Scalable, Cell-Based Method for the Functional Assessment of Ube3a Variants06:35

A Scalable, Cell-Based Method for the Functional Assessment of Ube3a Variants

Published on: October 10, 2022

2.3K
Navigating MARRVEL, a Web-Based Tool that Integrates Human Genomics and Model Organism Genetics Information09:37

Navigating MARRVEL, a Web-Based Tool that Integrates Human Genomics and Model Organism Genetics Information

Published on: August 15, 2019

10.2K

Related Concept Videos

Animal Mitochondrial Genetics02:59

Animal Mitochondrial Genetics

Among all the organelles in an animal cell, only mitochondria have their own independent genomes. Animal mitochondrial DNA is a double-stranded, closed-circular molecule with around 20,000 base pairs. Mitochondrial DNA is unique in that one of its two strands, the heavy, or H, -strand is guanine rich, whereas the complementary strand is cytosine rich and called the light, or L, -strand. Compared to nuclear DNA, mitochondrial DNA has a very low percentage of non-coding regions and is marked by...
8.8K
Incomplete Dominance01:43

Incomplete Dominance

Gregor Mendel's work (1822 - 1884) was primarily focused on pea plants. Through his initial experiments, he determined that every gene in a diploid cell has two variants called alleles inherited from each parent. He suggested that amongst these two alleles, one allele is dominant in character and the other recessive. The combination of alleles determines the phenotype of a gene in an organism.
29.4K
Mitochondrial Precursor Proteins01:39

Mitochondrial Precursor Proteins

Mitochondrial precursors are partially unfolded or loosely folded polypeptide chains. Newly synthesized precursors are inhibited from spontaneously folding into their native conformation by the cytosolic chaperones, heat shock proteins 70 (Hsp70), and mitochondrial import stimulation factors (MSFs). Precursors bound to MSFs are guided to the TOM70-TOM37 receptors, while precursors bound to Hsp70  chaperones are targetted to TOM20-TOM22 receptor complexes.
Most of the mitochondrial...
3.4K
ATP Synthase: Mechanism01:48

ATP Synthase: Mechanism

In animals, the mitochondrial F1F0 ATP synthase is the key protein that synthesizes ATP molecules through a complex catalytic mechanism. While the nuclear genome encodes the majority of ATP synthase subunits, the mitochondrial genome encodes some of the enzyme's most critical components. The formation of this multi-subunit enzyme is a complex multi-step process regulated at the level of transcription, translation, and assembly. Defects in one or more of these steps can result in decreased...
16.4K
Inborn Errors of Metabolism01:20

Inborn Errors of Metabolism

Phenylketonuria (PKU) is a protein metabolism disorder characterized by high blood levels of the amino acid phenylalanine. This results from a mutation in the gene responsible for phenylalanine hydroxylase, an enzyme that converts phenylalanine into tyrosine. When this enzyme is deficient, phenylalanine builds up in the blood, leading to symptoms such as vomiting, rashes, seizures, growth deficiency, and severe mental retardation. An early diagnosis and a diet restricting phenylalanine intake...
626
Cystic Fibrosis: Pathogenesis01:23

Cystic Fibrosis: Pathogenesis

Cystic fibrosis (CF), an autosomal recessive disorder, significantly affects the function of exocrine glands. This genetically inherited disease is characterized by the production of thick and sticky mucus, which can severely affect various organs and systems in the body.
CF is primarily caused by a genetic mutation in a chromosome 7 gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The most common gene mutation leading to CF is the ΔF508 mutation,...
644