Alternative titles; symbols
HGNC Approved Gene Symbol: NDUFB11
Cytogenetic location: Xp11.3 Genomic coordinates (GRCh38): X:47,142,216-47,145,491 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xp11.3 | ?Mitochondrial complex I deficiency, nuclear type 30 | 301021 | X-linked | 3 |
| Linear skin defects with multiple congenital anomalies 3 | 300952 | X-linked dominant | 3 |
NDUFB11 is a component of mitochondrial complex I. Complex I catalyzes the first step in the electron transport chain, the transfer of 2 electrons from NADH to ubiquinone, coupled to the translocation of 4 protons across the membrane (summary by Carroll et al., 2002).
By searching an EST database using mouse Np15.6 as query, followed by PCR and screening of a fetal brain cDNA library, Cui et al. (1999) cloned a full-length cDNA encoding human p17.3. The deduced 153-amino acid protein has a calculated molecular mass of 17.3 kD and contains a typical PEST region found in rapidly degraded proteins. The 3-prime untranslated region contains an atypical polyadenylation signal (ATTAAA). The p17.3 protein shares 81% identity with the mouse Np15.6 protein. Northern blot analysis revealed a 0.6-kb transcript that was expressed, in decreasing order of abundance, in prostate, pancreas, colon, heart, skeletal muscle, kidney, thymus, spleen, small intestine, brain, liver, testis, peripheral blood leukocytes, ovary, placenta, and lung.
Carroll et al. (2002) cloned bovine Ndufb11, which they called Esss, and identified human NDUFB11 by database analysis. The bovine and human proteins share 86% amino acid identity. The bovine protein has an incomplete mitochondrial import sequence and a membrane-spanning helix, but its PEST region is invalidated by an internal arginine. Human NDUFB11 has a complete mitochondrial import sequence.
Gross (2015) mapped the NDUFB11 gene to chromosome Xp11.3 based on an alignment of the NDUFB11 sequence (GenBank AF251063) with the genomic sequence (GRCh38).
Linear Skin Defects, Cardiomyopathy, and Various Other Congenital Anomalies
In 2 unrelated girls with linear skin defects, cardiomyopathy, and various other congenital anomalies (LSDMCA3; 300952), van Rahden et al. (2015) identified heterozygosity for truncating mutations in the NDUFB11 gene (R88X, 300403.0001 and c.402delG, 300403.0002). Both affected individuals as well as an unaffected carrier mother showed a highly skewed pattern of X-chromosome inactivation. By shRNA-mediated NDUFB11 knockdown in HeLa cells, van Rahden et al. (2015) demonstrated that NDUFB11 is essential for assembly and activity of complex I in the mitochondrial respiratory chain, as well as for cell growth and survival.
Mitochondrial Complex I Deficiency, Nuclear Type 30
In a male infant (patient 067) with lethal mitochondrial complex I deficiency nuclear type 30 (MC1DN30; 301021), Kohda et al. (2016) identified a de novo hemizygous missense mutation in the NDUFB11 gene (E121K; 300403.0003). The mutation, which was found by high-throughput exome sequencing of 142 patients with childhood-onset mitochondrial respiratory chain disorders, was confirmed by Sanger sequencing. Western blot analysis of patient fibroblasts showed no detectable NDUFB11 protein.
Kohda et al. (2016) found that knockdown of the Ndufb11 gene in Drosophila resulted in significantly reduced lifespan, decreased metabolic rate, loss of mitochondrial complex I assembly, and increased lactate and pyruvate.
In a female infant with linear skin defects, cardiomyopathy, and other congenital anomalies (LSDMCA3; 300952), van Rahden et al. (2015) identified heterozygosity for a de novo c.262C-T transition (c.262C-T, NM_019056.6) in exon 2 of the NDUFB11 gene, resulting in an arg88-to-ter (R88X) substitution upstream of an alternative splice donor site. At 6 months of age, the proband was hospitalized after cardiac arrest and underwent repeated treatment of ventricular fibrillation and tachycardia, but died within a few weeks; autopsy revealed histiocytoid cardiomyopathy. Leukocyte-derived DNA from the proband showed a highly skewed X-chromosome inactivation pattern (XCI, 10:90), whereas her healthy mother, who did not carry the mutation, had a less skewed XCI ratio (20:80). By shRNA-mediated NDUFB11 knockdown in HeLa cells, van Rahden et al. (2015) demonstrated that a reduced amount of NDUFB11 is associated with slower cell growth and increased apoptosis, suggesting that cells expressing mutant NDUFB11 are likely to be offset by those expressing the normal allele and eventually to be selected out.
In a 15-month-old girl with linear skin defects, cardiomyopathy, and other congenital anomalies (LSDMCA3; 300952), van Rahden et al. (2015) identified heterozygosity for a 1-bp deletion (c.402delG, NM_019056.6) in exon 3 of the NDUFB11 gene, causing a frameshift predicted to result in a premature termination codon (Arg134SerfsTer3). Her unaffected mother was heterozygous for the 1-bp deletion, as was an aborted affected female fetus. Peripheral blood cells from the proband and her mother exhibited complete skewing of X-chromosome inactivation (XCI), with a ratio of 100:0; DNA from the aborted fetus showed an XCI ratio of 99:1. By shRNA-mediated NDUFB11 knockdown in HeLa cells, van Rahden et al. (2015) demonstrated that a reduced amount of NDUFB11 is associated with slower cell growth and increased apoptosis, suggesting that cells expressing mutant NDUFB11 are likely to be offset by those expressing the normal allele and eventually to be selected out.
In a male infant (patient 067) with lethal mitochondrial complex I deficiency nuclear type 30 (MC1DN30; 301021), Kohda et al. (2016) identified a de novo hemizygous c.361G-A transition (c.361G-A, NM_001135998) in the NDUFB11 gene, resulting in a glu121-to-lys (E121K) substitution at a highly conserved residue. The mutation was found by high-throughput exome sequencing and confirmed by Sanger sequencing. The variant was filtered against the dbSNP (build 137), Exome Sequencing Project (ESP6500), and ExAC (February 2014) databases. Western blot analysis of patient fibroblasts showed no detectable NDUFB11 protein. Knockdown of the Ndufb11 gene in Drosophila resulted in significantly reduced lifespan, decreased metabolic rate, loss of mitochondrial complex I assembly, and increased lactate and pyruvate. The patient had intrauterine growth restriction, premature birth, heart failure, respiratory failure, metabolic acidosis, and mitochondrial complex I deficiency; he died at 55 hours of age. He had redundant skin but no linear skin defects.
Carroll, J., Shannon, R. J., Fearnley, I. M., Walker, J. E., Hirst, J. Definition of the nuclear encoded protein composition of bovine heart mitochondrial complex I: identification of two new subunits. J. Biol. Chem. 277: 50311-50317, 2002. [PubMed: 12381726] [Full Text: https://doi.org/10.1074/jbc.M209166200]
Cui, Y., Yu, L., Gong, R., Zhang, M., Fan, Y., Yue, P., Zhao, S. Cloning and tissue expressional characterization of a full-length cDNA encoding human neuronal protein P17.3. Biochem. Genet. 37: 175-185, 1999. [PubMed: 10544803] [Full Text: https://doi.org/10.1023/a:1018734605214]
Gross, M. B. Personal Communication. Baltimore, Md. 5/15/2015.
Kohda, M., Tokuzawa, Y., Kishita, Y., Nyuzuki, H., Moriyama, Y., Mizuno, Y., Hirata, T., Yatsuka, Y., Yamashita-Sugahara, Y., Nakachi, Y., Kato, H., Okuda, A., and 23 others. A comprehensive genomic analysis reveals the genetic landscape of mitochondrial respiratory chain complex deficiencies. PLoS Genet. 12: e1005679, 2016. Note: Electronic Article. [PubMed: 26741492] [Full Text: https://doi.org/10.1371/journal.pgen.1005679]
van Rahden, V. A., Fernandez-Vizarra, E., Alawi, M., Brand, K., Fellmann, F., Horn, D., Zeviani, M., Kutsche, K. Mutations in NDUFB11, encoding a complex I component of the mitochondrial respiratory chain, cause microphthalmia with linear skin defects syndrome. Am. J. Hum. Genet. 96: 640-650, 2015. [PubMed: 25772934] [Full Text: https://doi.org/10.1016/j.ajhg.2015.02.002]