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A novel TRMT5 mutation causes a complex inherited neuropathy syndrome: The role of nerve pathology in defining a demyelinating neuropathy
Author(s) -
ArgenteEscrig Herminia,
Vílchez Juan J.,
Frasquet Marina,
Muelas Nuria,
Azorín Inmaculada,
Vílchez Roger,
MilletSancho Elvira,
Pitarch Inmaculada,
TomásVila Miguel,
VázquezCosta Juan F.,
MasEstellés Fernando,
MarcoMarín Clara,
Espinós Carmen,
SerranoLorenzo Pablo,
Martin Miguel A.,
Lupo Vincenzo,
Sevilla Teresa
Publication year - 2022
Publication title -
neuropathology and applied neurobiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.538
H-Index - 95
eISSN - 1365-2990
pISSN - 0305-1846
DOI - 10.1111/nan.12817
Subject(s) - missense mutation , exome sequencing , mitochondrial respiratory chain , frameshift mutation , medicine , mutation , genetics , pathology , biology , gene , mitochondrion
Abstract Aims We aim to present data obtained from three patients belonging to three unrelated families with an infantile onset demyelinating neuropathy associated to somatic and neurodevelopmental delay and to describe the underlying genetic changes. Methods We performed whole‐exome sequencing on genomic DNA from the patients and their parents and reviewed the clinical, muscle and nerve data, the serial neurophysiological studies, brain and muscle MRIs, as well as the respiratory chain complex activity in the muscle of the three index patients. Computer modelling was used to characterise the new missense variant detected. Results All three patients had a short stature, delayed motor milestone acquisition, intellectual disability and cerebellar abnormalities associated with a severe demyelinating neuropathy, with distinct morphological features. Despite the proliferation of giant mitochondria, the mitochondrial respiratory chain complex activity in skeletal muscle was normal, except in one patient in whom there was a mild decrease in complex I enzyme activity. All three patients carried the same two compound heterozygous variants of the TRMT5 (tRNA Methyltransferase 5) gene, one known pathogenic frameshift mutation [c.312_315del (p.Ile105Serfs*4)] and a second rare missense change [c.665 T > C (p.Ile222Thr)]. TRMT5 is a nuclear‐encoded protein involved in the post‐transcriptional maturation of mitochondrial tRNA. Computer modelling of the human TRMT5 protein structure suggests that the rare p.Ile222Thr mutation could affect the stability of tRNA binding. Conclusions Our study expands the phenotype of mitochondrial disorders caused by TRTM5 mutations and defines a new form of recessive demyelinating peripheral neuropathy.