Alternative titles; symbolsCOMPLEX V, ATP SYNTHASE, SUBUNIT ATPase 8; ATP8Other entities represented in this entry:MITOCHONDRIAL COMPLEX V (ATP SYNTHASE) DEFICIE...
Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: MT-ATP8
Subunit 8 of mitochondrial ATP synthase (complex V) is encoded by nucleotides 8366-8572 of the mitochondrial genome.
For a discussion of genetic heterogeneity of mitochondrial complex V deficiency, see 614053.
▼ Molecular Genetics
In 4 unrelated infants who presented with isolated hypertrophic cardiomyopathy and congestive heart failure (500006), who later developed severe feeding difficulties and failure to thrive, Ware et al. (2009) identified an 8528T-C transition, resulting in concurrent changes in the overlapping MTATP6 and MTATP8 genes, M1T (516060.0010) and W55R (516070.0003), respectively. Ware et al. (2009) stated that this was the first description of a mitochondrial mutation affecting both complex V genes.
▼ Animal Model
Yu et al. (2009) identified a polymorphism in the mouse mitochondrial genome, G-T at position 7778, which resulted in an aspartic acid-to-tyrosine (D-Y) substitution in the fifth amino acid of the highly conserved N terminus of Mtatp8. Among a series of conplastic strains, the polymorphism increased susceptibility to multiple autoimmune diseases, including collagen-induced arthritis, autoimmune diabetes, nephritis, and autoimmune pancreatitis. Reproductive performance in females of the MRL/MpJ strain was impaired. The polymorphism also altered mitochondrial performance, increased peroxide production, and affected mitochondrial structure. The polymorphism increased the CD4 T-cell adaptive potential to an oxidative phosphorylation-impaired condition. The authors proposed a role for the mitochondria in autoimmunity and reproduction.
▼ ALLELIC VARIANTS ( 3 Selected Examples):
.0001 BRAIN PSEUDOATROPHY, REVERSIBLE, VALPROATE-INDUCED, SUSCEPTIBILITY TO
Galimberti et al. (2006) reported a Caucasian boy with mild learning difficulty and seizures treated with valproate therapy at age 8 years. During 2 years of valproate treatment, he showed increased irritability and learning difficulties, worsening sleep and EEG anomalies, and neuropsychologic decline. Brain MRI showed enlargement of the lateral ventricles and cerebral and cerebellar cortical sulci. At age 10 years, discontinuation of valproate led to clinical improvement over 3 months. Genetic analysis detected a heteroplasmic 8383C-T transition in the MTATP8 gene, resulting in a pro-to-ser substitution, in the boy, his unaffected mother and grandmother, and in a maternal uncle with rare generalized seizures who was not exposed to valproate. Galimberti et al. (2006) noted that Lam et al. (1997) had reported another patient with encephalopathy triggered by valproate therapy who was found to have a mutation in the MTTL1 gene (590050.0001).
.0002 CARDIOMYOPATHY, APICAL HYPERTROPHIC, AND NEUROPATHY
In a 16-year-old boy with apical hypertrophic cardiomyopathy and neuropathy, Jonckheere et al. (2008) identified a homoplasmic 8529G-A transition in the MTATP8 gene, resulting in a trp55-to-ter (W55X) substitution. The patient was the third child of nonconsanguineous parents, with 2 healthy sibs. Examination at age 16 years revealed dysarthric speech, ataxic gait, positive Trendelenburg sign, reduced tendon reflexes, and bilateral Babinski sign. Cardiac evaluation showed left ventricular hypertrophy concentrated around the apex of the left ventricle. Sensory and motor axonal polyneuropathy was seen on electromyelogram. Reduced complex V activity was measured in the patient's fibroblasts and muscle tissue, and was confirmed in cybrid clones containing patient-derived mitochondrial DNA. Immunoblotting after blue native polyacrylamide gel electrophoresis showed a lack of holocomplex V and increased amounts of mitochondrial ATP synthase subcomplexes. An in-gel activity assay of ATP hydrolysis showed activity of free F(1)-ATPase in the patient's muscle tissue and in the cybrid clones.
.0003 CARDIOMYOPATHY, INFANTILE HYPERTROPHIC
In 4 unrelated infants who presented with hypertrophic cardiomyopathy and congestive heart failure (500006), Ware et al. (2009) identified a heteroplasmic 8528T-C transition, resulting in concurrent substitutions in the overlapping MTATP6 and MTATP8 genes: a met1-to-thr (M1W) substitution in MTATP6 (516060.0010), predicted to abrogate the start of translation, and a trp55-to-arg (W55R) substitution at a highly conserved residue in MTATP8. The alteration appeared homoplasmic on sequence analysis; however, tissue analysis of 1 patient and her asymptomatic mother and maternal aunt revealed that the patient carried a high degree of heteroplasmic mutation (92 to 98%) in all 5 tissues examined, whereas her mother carried the heteroplasmic mutation at a much lower level (15 to 25%), and the mutation was not detected in her maternal aunt. Functional analysis in skin fibroblasts from this patient and her mother indicated a significant decrease in ATP synthesis in the patient.