DO: 0070446;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 17q23.3 | ?Mitochondrial DNA depletion syndrome 16 (hepatic type) | 618528 | Autosomal recessive | 3 | POLG2 | 604983 |
A number sign (#) is used with this entry because of evidence that mitochondrial DNA depletion syndrome-16 (MTDPS16) is caused by homozygous mutation in the POLG2 gene (604983) on chromosome 17q23. One such patient has been reported.
For a discussion of genetic heterogeneity of autosomal recessive mtDNA depletion syndromes, see MTDPS1 (603041).
Varma et al. (2016) reported a 3-month-old boy with fulminant neonatal hepatic failure resulting in death at 9 months of age (Hoff et al., 2018). The patient presented with poor feeding, difficulty breathing, and abdominal distention. Laboratory studies showed profound metabolic acidosis, increased lactate, hyperkalemia, elevated liver enzymes, elevated total bilirubin and bile acids, decreased albumin, and coagulopathy. He also an abnormal carnitine profile, suggesting mitochondrial dysfunction. Liver biopsy showed microvesicular steatosis, cholestasis, and panlobular fibrosis, as well as abnormally shaped mitochondria. Severe mtDNA depletion was seen in the liver (25% of control levels), muscle (20%), and blood leukocytes (44%). Muscle biopsy was essentially normal aside from mtDNA depletion and mild ultrastructural alterations in mitochondria. Neurologic examination was unremarkable and muscle tone was normal; brain imaging showed thin corpus callosum. Family history revealed that the mother of the proband had 2 early first trimester miscarriages and a stillbirth at 8 months.
The transmission pattern of MTDPS16 in the family reported by Varma et al. (2016) was consistent with autosomal recessive inheritance.
In a male infant with MTDPS16, Varma et al. (2016) identified a homozygous c.544C-T transition in the POLG2 gene, resulting in an arg182-to-trp (R182W) substitution (R182W; 604983.0006) at a residue in the dimerization base that is conserved in vertebrates. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was found in the heterozygous state in each unaffected parent, confirming segregation. The variant was not found in the 1000 Genomes Project, Exome Variant Server, or ExAC databases. Functional studies of the variant were not performed, but it was predicted to disrupt POLG2 homodimerization and cause loss of progressive mtDNA synthesis. Patient tissues showed variable degrees of mtDNA depletion.
Hoff et al. (2018) performed functional studies on the R182W variant. Patient-derived fibroblasts showed a growth defect associated with reduced mtDNA copy number and decreased mRNA levels of both POLG (174763) and POLG2 compared to controls. HEK293 cells transfected with the mutation showed defective oxidative phosphorylation, impaired respiratory activity, and decreased ATP production. The R182W protein showed similar DNA-binding abilities and association with POLG as wildtype POLG2. However, the mutant protein showed reduced thermostability, suggesting structural instability, and impaired ability to stimulate POLG compared to wildtype.
Hoff, K. E., DeBalsi, K. L., Sanchez-Quintero, M. J., Longley, M. J., Hirano, M., Naini, A. B., Copeland, W. C. Characterization of the human homozygous R182W POLG2 mutation in mitochondrial DNA depletion syndrome. PLoS One 13: e0203198, 2018. Note: Electronic Article. [PubMed: 30157269] [Full Text: https://doi.org/10.1371/journal.pone.0203198]
Varma, H., Faust, P. L., Iglesias, A. D., Lagana, S. M., Wou, K., Hirano, M., DiMauro, S., Mansukani, M. M., Hoff, K. E., Nagy, P. L., Copeland, W. C., Naini, A. B. Whole exome sequencing identifies a homozygous POLG2 missense variant in an infant with fulminant hepatic failure and mitochondrial DNA depletion. Europ. J. Med. Genet. 59: 540-545, 2016. [PubMed: 27592148] [Full Text: https://doi.org/10.1016/j.ejmg.2016.08.012]