Biallelic Mutations in MTPAP Associated with a Lethal Encephalopathy

Abstract

Background A homozygous founder mutation in MTPAP/TENT6, encoding mitochondrial poly(A) polymerase (MTPAP), was first reported in six individuals of Old Order Amish descent demonstrating an early-onset, progressive spastic ataxia with optic atrophy and learning difficulties. MTPAP contributes to the regulation of mitochondrial gene expression through the polyadenylation of mitochondrially encoded mRNAs. Mitochondrial mRNAs with severely truncated poly(A) tails were observed in affected individuals, and mitochondrial protein expression was altered. Objective To determine the genetic basis of a perinatal encephalopathy associated with stereotyped neuroimaging and infantile death in three patients from two unrelated families. Methods Whole-exome sequencing was performed in two unrelated patients and the unaffected parents of one of these individuals. Variants and familial segregation were confirmed by Sanger sequencing. Polyadenylation of mitochondrial transcripts and de novo synthesis of mitochondrial proteins were assessed in patient's fibroblasts. Results Compound heterozygous p.Ile428Thr and p.Arg523Trp substitutions in MTPAP were recorded in two affected siblings from one family, and a homozygous p.Ile385Phe missense variant identified in a further affected child from a second sibship. Mitochondrial poly(A) tail analysis demonstrated shorter posttranscriptional additions to the mitochondrial transcripts, as well as an altered expression of mitochondrial proteins in the fibroblasts of the two siblings compared with healthy controls. Conclusion Mutations in MTPAP likely cause an autosomal recessive perinatal encephalopathy with lethality in the first year of life.

Functions and mechanisms of RNA tailing by metazoan terminal nucleotidyltransferases

“…The same homozygous N478D mutation causes a distinct cellular phenotype that is characterized by DNA damage, impairments in DNA repair kinetics, and an increase in cell death following exposure to ionizing radiation (Martin et al, 2014). Other rare missense mutations of MTPAP (i.e., heterozygous I428T and R523W mutations and the homozygous I385F mutation) have been associated with autosomal recessive perinatal lethal encephalopathy (Van Eyck et al, 2019). For N478D, these mutations also lead to a decrease in the polyadenylation of mitochondrial transcripts and alterations of the expression of mitochondrially encoded proteins.…”

Mitochondrial diseases: expanding the diagnosis in the era of genetic testing

“…The other subunit mt-mRNAs are polyadenylated performed by mtPAP, a mitochondrial polyA polymerase encoded by MTPAP. Dysfunctional mtPAP produces range of disease, with a more common presentation of a progressive spastic ataxia, optic atrophy, and learning difficulties, but some variants also induce an early infantile death [173,174] . The leucine-rich pentatricopeptide repeat-containing protein (LRPPRC) is found mainly in the matrix, where it controls mRNA stability [175] .…”