Alternative titles; symbols
HGNC Approved Gene Symbol: MT-ND3
Subunit 3 is 1 of 7 mitochondrial DNA (mtDNA) encoded subunits (MTND1, MTND2, MTND3, MTND4, MTND4L, MTND5, MTND6) included among the approximately 41 polypeptides of respiratory Complex I (NADH:ubiquinone oxidoreductase, EC 1.6.5.3) (Shoffner and Wallace, 1995; Arizmendi et al., 1992; Walker et al., 1992; Anderson et al., 1981; Attardi et al., 1986; Chomyn et al. (1985, 1986); Wallace et al., 1986; Oliver and Wallace, 1982; Wallace et al., 1994). Complex I accepts electron from NADH, transfers them to ubiquinone (Coenzyme Q10) and uses the energy released to pump protons across the mitochondrial inner membrane. Complex I is more fully described under 516000. MTND3 has been localized to the hydrophobic protein fragment of the Complex (Ragan, 1987).
MTND3 is encoded by the guanine-rich heavy (H) strand of the mtDNA and located between nucleotide pairs (nps) 10059 and 10404 (Anderson et al., 1981; Wallace et al., 1994). It is maternally inherited along with the mtDNA (Giles et al., 1980; Case and Wallace, 1981).
The MTND3 gene encompasses 345 nps of continuous coding sequence. It contains no introns, begins with the AUG methionine codon, and ends with the U of the UAA stop codon (Anderson et al., 1981; Ojala et al., 1981; Montoya et al., 1981). It is transcribed as a part of the polycistronic H-strand transcript, flanked by the tRNA(Gly) and tRNA(Arg) transcripts. These tRNAs are cleaved from the RNA freeing transcript 17, the MTND3 mRNA. The mRNA is then polyadenylated completing the termination codon (Anderson et al., 1981; Ojala et al., 1981; Attardi et al., 1982).
The predicted polypeptide has a molecular weight of 13.2 kD (Anderson et al., 1981; Wallace et al., 1994). However, its apparent MW on SDS-polyacrylamide gel (PAGE) using Tris-glycine buffer is 13.5 kD (Oliver et al., 1984; Oliver and Wallace, 1982; Wallace et al., 1986) whereas on SDS-PAGE using urea-phosphate buffer it is 6 kD (Chomyn et al., 1983).
Several restriction site polymorphisms have been identified at the following nucleotide position for the indicated enzymes (where '+' = site gain, '-' = site loss relative to the reference sequence, Anderson et al., 1981): Dde I:+10394; Hae III:, +10097, -10364; Hha I: +10066; HinfI:-10256; Mbo I: -10254; Taq I: +10084, -10180, +10252 (Wallace et al., 1994).
A prominent polypeptide polymorphism has been identified in MTND3 from certain African-derived mtDNAs including that of HeLa cells (Yatscoff et al., 1978; Oliver and Wallace, 1982; Spinner and King, 1986; Wallace et al., 1982; Wallace et al., 1982). The polymorphism is the product of an A to G transition of np 10086, which changes an asparagine to an aspartate (N10D), placing a negatively charged amino acid within a stretch of 30 uncharged amino acids (Oliver et al., 1983). A second polymorphism at np 10398 (516002.0002) changes the penultimate amino acid from threonine to alanine (Oliver et al., 1983).
Mitochondrial Complex I Deficiency, Mitochondrial Type 1
In a patient with mitochondrial complex I deficiency (500014), Taylor et al. (2001) identified a heteroplasmic 10191T-C transition in the ND3 gene (S45P; 516002.0001).
In 3 unrelated patients with infantile encephalopathy and isolated complex I deficiency, 1 of whom had a phenotype consistent with Leigh syndrome (see 256000), McFarland et al. (2004) identified a heteroplasmic 10158T-C transition in the MTND3 gene (516002.0003).
Kirby et al. (2004) identified the 10158T-C mutation in 2 unrelated patients with isolated complex I deficiency, 1 of whom had a phenotype consistent with Leigh syndrome.
Sarzi et al. (2007) identified a 10197G-A transition (A47T; 516002.0004) in the MTND3 gene in 3 unrelated families with Leigh syndrome or dystonia.
Parkinson Disease
Van der Walt et al. (2003) genotyped 10 single-nucleotide polymorphisms that define the European mitochondrial DNA haplogroups in 609 white patients with Parkinson disease (556500) and 340 unaffected white control subjects. Overall, individuals classified as haplogroup J demonstrated a significant decrease in risk of Parkinson disease versus individuals carrying haplogroup H, the most common haplogroup. Furthermore, a specific SNP that defines these 2 haplogroups, 10398G (see 516002.0002), is strongly associated with this protective effect. The 10398G SNP causes a nonconservative amino acid change from threonine to alanine within the ND3 of complex I. After stratification by sex, this decrease in risk appeared stronger in women than in men. Van der Walt et al. (2003) concluded that ND3 may be an important factor in Parkinson disease susceptibility among white individuals and could help explain the role of complex I in Parkinson disease expression. Pyle et al. (2005) noted that the 10398A-G polymorphism has been described on several other haplotypes (see Herrnstadt et al., 2002), indicating that the 10398A-G polymorphism does not 'define' haplotypes J and K, as asserted by van der Walt et al. (2003).
Taylor et al. (2001) reported a patient who had onset of migraine symptoms associated with flashing lights in his vision and right arm weakness at age 24 years. He subsequently developed myoclonus, seizures, cognitive decline, ataxia, peripheral neuropathy, eye movement abnormalities, and optic atrophy. Muscle biopsy showed a deficit (40% of controls) in complex I activity (252010), but no ragged-red fibers. A heteroplasmic 10191T-C transition in the ND3 gene was identified in his skeletal muscle (77%) and blood (14%), as well as in his mother (3% in blood) and 2 unaffected sibs (barely detectable in blood). The mutation was not present in 90 other samples. Taylor et al. (2001) noted that the mutation changes a hydrophilic serine in codon 45 to a hydrophobic proline (S45P), which may affect the folding of the protein.
In a patient with infantile encephalopathy and complex I deficiency, McFarland et al. (2004) identified the 10191T-C transition. From birth, he was lethargic with hypotonia, areflexia, and muscle atrophy. Micrognathia and talipes equinovarus were noted.
Oliver et al. (1983) reported a polymorphism at nucleotide 10398 that changed the penultimate amino acid from threonine to alanine. In a study of Europeans with Parkinson disease (556500) compared with controls, the presence of the 10398G allele was associated with the protective effect of haplogroup J or K.
The role of mitochondria in causing diseases is largely attributed to its reactive oxygen species (ROS) production property. In the context of diabetes, ROS is suggested to trigger different forms of insulin resistance involving different mechanisms. The suggestive role of an mtDNA variant G10398A in increasing ROS production and the impaired response to oxidative stress due to the T16189C variant were studied by Bhat et al. (2007) as genetic susceptibility factors in type 2 diabetes mellitus (see 125853). In 2 North Indian population cohorts, a statistically significant association was observed for the 10398A allele, and analysis of the G10398A/T16189C haplotype demonstrated risk in both cohorts. The study suggested that 10398A and 16189C alleles provide susceptibility to T2DM independently as well as together.
In 3 unrelated patients with infantile encephalopathy and isolated complex I deficiency (500014), McFarland et al. (2004) identified a heteroplasmic 10158T-C transition in the MTND3 gene. One patient had a phenotype consistent with Leigh syndrome (256000), including increased blood and CSF lactate, delayed motor development, and bilateral thalamic lesions on MRI. The other 2 patients both had lactic acidosis in blood and CSF but one had hyperreflexia, clonus, and spastic quadriparesis, whereas the other had hypotonia and areflexia.
Kirby et al. (2004) identified the 10158T-C mutation in 2 unrelated patients with isolated complex I deficiency. One of the patients had lethal infantile mitochondrial disease and died at age 6 months; biochemical analysis showed 1% residual complex I activity. The other patient had a phenotype consistent with Leigh syndrome and died at age 3 years, 9 months; residual complex I activity was 14%.
In affected members of 3 unrelated families with Leigh syndrome (see 256000) or dystonia, Sarzi et al. (2007) identified a 10197G-A transition in the MTND3 gene, resulting in an ala47-to-thr (A47T) substitution in a highly conserved part of the ND3 subunit. The mutation was found to be homoplasmic in the most severely affected patients (children), whereas the mutant load varied from 50% in the leukocytes of a healthy mother to 67% and 74%, respectively, in the 2 mildly affected mothers. Sarzi et al. (2007) concluded that 10197G-A is a common mtDNA mutation responsible for Leigh syndrome and dystonia.
Chae et al. (2007) identified the 10197G-A mutation in 3 Korean patients with Leigh syndrome due to complex I deficiency (500014). Two sibs had childhood-onset progressive generalized dystonia, whereas the third unrelated child had stroke-like episodes in infancy. All 3 had bilateral lesions in the basal ganglia. Muscle biopsies showed 98%, 86%, and 80% heteroplasmy, respectively, for the mutation.
Wang et al. (2009) identified a homoplasmic 10197G-A mutation in 6 affected members of a Chinese Han family with Leber optic atrophy and dystonia (500001). The mutation occurred on mitochondrial haplogroup D4b. The proband, who was most severely affected, developed an abnormal gait at age 5 years after a bout of diarrhea. At age 14 years, he had painless and progressive visual loss, and lost ambulation due to dystonia. There was no evidence of mental or psychomotor retardation. By the third decade, he was unable to stand or speak clearly. Neurologic exam showed generalized spastic dystonia involving the limbs, trunk, neck, and face, with diffuse muscle wasting. Brain MRI showed abnormal signals in the basal ganglia. Other family members had a similar, but less severe, disease course with spastic gait, dystonia, visual loss, and basal ganglia lesions. Nine additional family members with a homoplasmic mutation had sudden onset of painless vision loss due to optic atrophy between ages 14 and 30 years, but without other symptoms. A tenth patient had loss of vision and was found to have postural tremor, hyperreflexia, and unstable gait. Two unaffected family members also carried the homoplasmic mutation, suggesting incomplete penetrance.
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