Mutation screening of 75 candidate genes in 152 complex I deficiency cases identifies pathogenic variants in 16 genes including NDUFB9.
BACKGROUND
Mitochondrial complex I deficiency is the most common cause of mitochondrial disease in childhood. Identification of the molecular basis is difficult given the clinical and genetic heterogeneity. Most patients lack a molecular definition in routine diagnostics.


METHODS
A large-scale mutation screen of 75 candidate genes in 152 patients with complex I deficiency was performed by high-resolution melting curve analysis and Sanger sequencing. The causal role of a new disease allele was confirmed by functional complementation assays. The clinical phenotype of patients carrying mutations was documented using a standardised questionnaire.


RESULTS
Causative mutations were detected in 16 genes, 15 of which had previously been associated with complex I deficiency: three mitochondrial DNA genes encoding complex I subunits, two mitochondrial tRNA genes and nuclear DNA genes encoding six complex I subunits and four assembly factors. For the first time, a causal mutation is described in NDUFB9, coding for a complex I subunit, resulting in reduction in NDUFB9 protein and both amount and activity of complex I. These features were rescued by expression of wild-type NDUFB9 in patient-derived fibroblasts.


CONCLUSIONS
Mutant NDUFB9 is a new cause of complex I deficiency. A molecular diagnosis related to complex I deficiency was established in 18% of patients. However, most patients are likely to carry mutations in genes so far not associated with complex I function. The authors conclude that the high degree of genetic heterogeneity in complex I disorders warrants the implementation of unbiased genome-wide strategies for the complete molecular dissection of mitochondrial complex I deficiency.
Institute of Human Genetics, Technische Universität München, Munich, Germany.
Tobias B
TB
Haack
Florence
F
Madignier
Martina
M
Herzer
Eleonora
E
Lamantea
Katharina
K
Danhauser
Federica
F
Invernizzi
Johannes
J
Koch
Martin
M
Freitag
Rene
R
Drost
Ingo
I
Hillier
Birgit
B
Haberberger
Johannes A
JA
Mayr
Uwe
U
Ahting
Valeria
V
Tiranti
Agnes
A
Rötig
Arcangela
A
Iuso
Rita
R
Horvath
Marketa
M
Tesarova
Ivo
I
Baric
Graziella
G
Uziel
Boris
B
Rolinski
Wolfgang
W
Sperl
Thomas
T
Meitinger
Massimo
M
Zeviani
Peter
P
Freisinger
Holger
H
Prokisch
D004252:DNA Mutational Analysis; D042967:Electron Transport Complex I / Q000172:deficiency / Q000235:genetics; D050259:Genes, Mitochondrial; D018740:Genetic Heterogeneity; D057166:High-Throughput Screening Assays; D006801:Humans; D028361:Mitochondrial Diseases / Q000175:diagnosis / Q000235:genetics*; D009154:Mutation; D009245:NADH Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype
D009245:NADH Dehydrogenase; D042967:Electron Transport Complex I; C118906:NDUFB9 protein, human