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A novel TRMT5 mutation causes a complex inherited neuropathy syndrome: The role of nerve pathology in defining a demyelinating neuropathy

Fecha de publicación: Fecha Ahead of Print:

Autores de CIPF

Participantes ajenos a CIPF

  • Argente-Escrig, H
  • Vilchez, JJ
  • Frasquet, M
  • Muelas, N
  • Azorin, I
  • Vilchez, R
  • Millet-Sancho, E
  • Pitarch, I
  • Tomas-Vila, M
  • Vazquez-Costa, JF
  • Mas-Estelles, F
  • Marco-Marin, C
  • Serrano-Lorenzo, P
  • Martin, MA
  • Lupo, V
  • Sevilla, T

Grupos de Investigación

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.

Datos de la publicación

ISSN/ISSNe:
0305-1846, 1365-2990

NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY  Blackwell Publishing Inc.

Tipo:
Article
Páginas:
-
PubMed:
35342985

Citas Recibidas en Web of Science: 10

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Keywords

  • inherited neuropathy; mitochondrial disorders; mitochondrial neuropathies; TRMT5

Financiación

Fondo Europeo de Desarrollo Regional
Fundacion Isabel Gemio
Generalitat Valenciana (PROMETEO/2018/13)
Instituto de Salud Carlos III (PI16/00403)
Instituto de Salud Carlos III (PI18/01374)
Instituto de Salud Carlos III (PI19/01178)

Proyectos asociados

PID10470. No se ingresará dinero en el CIPF. La ayuda consiste en un estudio genómico (long & read-sequencing) para 25 muestras.

Investigador Principal: CARMEN ESPINÓS ARMERO

EASI- Genomics . 2020

Estudios clínicos, bases genéticas y biomarcadores pronóstico en enfermedades raras neurodegenerativas

Investigador Principal: CARMEN ESPINÓS ARMERO

INSTITUTO DE SALUD CARLOS III . 2022

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