Background
Spinocerebellar ataxias (SCAs) are genetically, clinically and pathologically heterogeneous diseases characterized by progressive cerebellar ataxia variably associated with dysarthria, oculomotor abnormalities, epilepsy, and mental impairment. Neuronal loss is observed in cerebellum and brainstem pathologies, and neuroimaging demonstrates the atrophy of those regions. These pathologies can be caused by autosomal dominant, autosomal recessive, and X-linked mutations, and many of the dominant mutations are caused by CAG triplet repeat expansion. Thirteen recessive SCAs (numbered as SCAR1-13) have been reported, and causative genes have been identified for 7 of them.
In recent years, it has been reported that cases of neurodegenerative disease associated with atrophy of the cerebellar vermis and the cerebral cortex are caused by homozygous nonsense mutations of
TTC19 [GenBank:NM_017775] in Italian and Portuguese families [
1,
2].
TTC19 encodes tetratricopeptide repeat domain 19 which consists of 380 amino acids.
TTC19 is involved in the assembly and activity of ubiquinol-cytochrome
c reductase (mitochondrial respiratory chain complex III, E.C.1.10.2.2) (MRC cIII). Mammalian cIII consists of 11 subunits [
3]. Among them, cytochrome
b is the only gene encoded by mitochondrial DNA; all other subunits are encoded by nuclear DNA. Mutations in
BCS1L[
4], one of the assembly factors, are involved in most cases of cIII deficiency. According to the report mentioned above [
1], the TTC19 protein is another assembly factor of cIII, and nonsense mutations in its gene cause the functional loss of cIII and, consequently, neurodegenerative disease.
Here, we performed exome sequencing on a patient clinically diagnosed with recessive SCA and identified a novel
TTC19 mutation. Her main symptoms were cerebellar ataxia and mental impairment, and magnetic resonance imaging (MRI) results were similar to those described in previous reports [
1,
2].
Discussion
This report describes a
TTC19 mutation causing ataxia and metal impairment in an Asian population. According to the previous reports, all patients harbored homozygous nonsense mutations in
TTC19, and head MRI showed characteristic findings including cerebellar atrophy and abnormal intensity at the bilateral inferior olives [
1,
2]. Our patient had a novel homozygous nonsense mutation of
TTC19, and head MRI were quite similar to those previously reported. The TTC19 protein is an assembly factor of MRC cIII, which transfers electrons from coenzyme Q to cytochrome
c. TTC19 mutations lead to mitochondrial dysfunction, which causes increased levels of blood lactic acid. Simultaneously, magnetic resonance spectroscopy shows a lactic peak [
1]. While the patient’s head MRI revealed abnormal features, her blood lactic acid and pyruvic acid levels were normal. However, these acid levels were elevated 6 years after the disease onset. One should consider mitochondrial abnormality and perform genetic analysis when observing such MRI characteristics. In the previous studies, no TTC19 protein was detected and the TTC19 transcript level was markedly reduced in samples with
TTC19 mutations [
1,
2]. However, further analysis could not be performed because we could not obtain any additional clinical specimens from the patient other than gDNA.
We identified one heterozygote for this mutation in control samples. This result indicates an allele frequency of 0.14%, but this mutation was not included in public SNP databases such as dbSNP and 1000 genomes. Therefore, the actual frequency of the mutation is even lower, which does not rule out the possibility that the mutation is a cause of recessive inheritance of the symptoms observed in the patient.
Neurodegeneration caused by mutations of
TTC19 are classified as mitochondrial complex III deficiencies (MC3DNs), including MC3DN1 [MIM:124000] [
4], which is associated with compound heterozygous or homozygous mutations of the
BCS1L gene. Clinical symptoms of MC3DN are varied, but in reports on mutations of
TTC19, many cases exhibit neurological disorders in adulthood, and some cases present both hemiplegia and cerebellar ataxia. Pyramidal signs were not observed in our case, but intellectual dysfunction was observed. As shown in previous reports, TTC19 p.Q173Rfs*4, p.L219* [
1] and p.A200Afs*8 [
2] are located between the first and the second TPR domains, but p.Q277*, the novel substitution we identified is located between the second and third domains, accordingly deleting half of the TPR domains. Notably, all these mutations are nonsense mutations. Clinical symptoms were mild compared with the symptoms from previously reported cases, but determining whether mutations are associated with clinical symptoms may require a longer observation of our patient’s clinical course and the accumulation of more cases.
Regarding other variant candidates, the
NPM2 variant was predicted as benign by PolyPhen-2, Mutation Taster, and SIFT; the
ZSCAN4 variant was predicted as damaging only by SIFT. Thus, it is unlikely that
NPM2 or
ZSCAN4 is the causative mutation. The
PDLIM2 variant was predicted as disease causing by Mutation Taster and SIFT. However, it is unlikely that
PDLIM2 is the cause of SCA because PDLIM2 is expressed at low levels in the brain and is speculated to be associated with the inflammatory response of T helper 17 cells [
14,
15].
Several studies have implicated mutations in genes involved in mitochondrial function as a cause of SCAs [
16]. For example, coenzyme Q10 deficiencies are known as diseases that lead to ataxia associated with MRC dysfunction. Thus far, there have been 6 subtypes of coenzyme Q10 deficiencies, including COQ10D4 [MIM:612016], which is also referred to as SCAR9 and is caused by homozygous or compound heterozygous mutations in
CABC1[
17]. In addition to cerebellar ataxia, coenzyme Q10 deficiencies show hypotonia, epilepsy, and muscular symptoms. Thus, mutations in the genes causing mitochondrial dysfunction show broad spectrum of clinical outcome.
Conclusions
In conclusion, using exome sequencing, we identified a new TTC19 mutation that is the cause of an autosomal recessive SCA. Notably, our case showed abnormal MRI findings before we detected a metabolic disorder. Genes associated with mitochondrial function cause many types of SCAs, and we should consider the genetic analysis of mitochondria-related genes when observing such characteristic clinical features including MRI abnormalities.
Acknowledgements
This work was supported in part by the Funding Program for Next Generation World-Leading Researchers from the Cabinet Office of the Government of Japan (HMa), a Grant-in-Aid for Scientific Research on Innovative Areas (Brain Environment) from the Ministry of Education, Science, Sports and Culture of Japan (HK), and a Grant-in-Aid from the Research Committee of CNS Degenerative Diseases from the Ministry of Health, Labour and Welfare of Japan (HK).
Competing interests
Dr. Morino, Dr. Miyamoto, Dr. Ohnishi, Dr. Maruyama and Dr. Kawakami report no conflicts of interest.
Authors’ contributions
HMo contributed substantially to conception and design, the acquisition of data, the analysis and interpretation of data, and the drafting of the article. RM participated in the acquisition of data, as well as the analysis and interpretation of the data. SO participated in the acquisition of samples and clinical data. HMa substantially contributed to conception and design, drafting the article, and the acquisition of funding. HK substantially contributed to conception and design, the acquisition of data, the acquisition of funding, and general supervision of the research group. All authors critically revised the article for important intellectual contents, and approved the final manuscript.