Biallelic Mutations in DNM1L are Associated with a Slowly Progressive Infantile Encephalopathy

Alessia Nasca, Andrea Legati, Enrico Baruffini, Cecilia Nolli, Isabella Moroni, Anna Ardissone, Paola Goffrini, Daniele Ghezzi

Research output: Contribution to journalArticle

Abstract

Mitochondria are highly dynamic organelles, undergoing continuous fission and fusion, and mitochondrial dynamics is important for several cellular functions. DNM1L is the most important mediator of mitochondrial fission, with a role also in peroxisome division. Few reports of patients with genetic defects in DNM1L have been published, most of them describing de novo dominant mutations. We identified compound heterozygous DNM1L variants in two brothers presenting with an infantile slowly progressive neurological impairment. One variant was a frame-shift mutation, the other was a missense change, the pathogenicity of which was validated in a yeast model. Fluorescence microscopy revealed abnormally elongated mitochondria and aberrant peroxisomes in mutant fibroblasts, indicating impaired fission of these organelles. In conclusion, we described a recessive disease caused by DNM1L mutations, with a clinical phenotype resembling mitochondrial disorders but without any biochemical features typical of these syndromes (lactic acidosis, respiratory chain complex deficiency) or indicating a peroxisomal disorder.

Original languageEnglish
Pages (from-to)898-903
Number of pages6
JournalHuman Mutation
Volume37
Issue number9
DOIs
Publication statusPublished - Sep 1 2016

Fingerprint

Mitochondrial Dynamics
Peroxisomes
Brain Diseases
Organelles
Mitochondria
Peroxisomal Disorders
Mitochondrial Diseases
Lactic Acidosis
Frameshift Mutation
Mutation
Electron Transport
Fluorescence Microscopy
Virulence
Siblings
Fibroblasts
Yeasts
Phenotype

Keywords

  • DNM1L
  • mitochondrial disorders
  • mitochondrial dynamics
  • mitochondrial fission
  • peroxisome

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Biallelic Mutations in DNM1L are Associated with a Slowly Progressive Infantile Encephalopathy. / Nasca, Alessia; Legati, Andrea; Baruffini, Enrico; Nolli, Cecilia; Moroni, Isabella; Ardissone, Anna; Goffrini, Paola; Ghezzi, Daniele.

In: Human Mutation, Vol. 37, No. 9, 01.09.2016, p. 898-903.

Research output: Contribution to journalArticle

Nasca, Alessia ; Legati, Andrea ; Baruffini, Enrico ; Nolli, Cecilia ; Moroni, Isabella ; Ardissone, Anna ; Goffrini, Paola ; Ghezzi, Daniele. / Biallelic Mutations in DNM1L are Associated with a Slowly Progressive Infantile Encephalopathy. In: Human Mutation. 2016 ; Vol. 37, No. 9. pp. 898-903.
@article{33159bdc85314db4bd592d76937fbcae,
title = "Biallelic Mutations in DNM1L are Associated with a Slowly Progressive Infantile Encephalopathy",
abstract = "Mitochondria are highly dynamic organelles, undergoing continuous fission and fusion, and mitochondrial dynamics is important for several cellular functions. DNM1L is the most important mediator of mitochondrial fission, with a role also in peroxisome division. Few reports of patients with genetic defects in DNM1L have been published, most of them describing de novo dominant mutations. We identified compound heterozygous DNM1L variants in two brothers presenting with an infantile slowly progressive neurological impairment. One variant was a frame-shift mutation, the other was a missense change, the pathogenicity of which was validated in a yeast model. Fluorescence microscopy revealed abnormally elongated mitochondria and aberrant peroxisomes in mutant fibroblasts, indicating impaired fission of these organelles. In conclusion, we described a recessive disease caused by DNM1L mutations, with a clinical phenotype resembling mitochondrial disorders but without any biochemical features typical of these syndromes (lactic acidosis, respiratory chain complex deficiency) or indicating a peroxisomal disorder.",
keywords = "DNM1L, mitochondrial disorders, mitochondrial dynamics, mitochondrial fission, peroxisome",
author = "Alessia Nasca and Andrea Legati and Enrico Baruffini and Cecilia Nolli and Isabella Moroni and Anna Ardissone and Paola Goffrini and Daniele Ghezzi",
year = "2016",
month = "9",
day = "1",
doi = "10.1002/humu.23033",
language = "English",
volume = "37",
pages = "898--903",
journal = "Human Mutation",
issn = "1059-7794",
publisher = "John Wiley and Sons Inc.",
number = "9",

}

TY - JOUR

T1 - Biallelic Mutations in DNM1L are Associated with a Slowly Progressive Infantile Encephalopathy

AU - Nasca, Alessia

AU - Legati, Andrea

AU - Baruffini, Enrico

AU - Nolli, Cecilia

AU - Moroni, Isabella

AU - Ardissone, Anna

AU - Goffrini, Paola

AU - Ghezzi, Daniele

PY - 2016/9/1

Y1 - 2016/9/1

N2 - Mitochondria are highly dynamic organelles, undergoing continuous fission and fusion, and mitochondrial dynamics is important for several cellular functions. DNM1L is the most important mediator of mitochondrial fission, with a role also in peroxisome division. Few reports of patients with genetic defects in DNM1L have been published, most of them describing de novo dominant mutations. We identified compound heterozygous DNM1L variants in two brothers presenting with an infantile slowly progressive neurological impairment. One variant was a frame-shift mutation, the other was a missense change, the pathogenicity of which was validated in a yeast model. Fluorescence microscopy revealed abnormally elongated mitochondria and aberrant peroxisomes in mutant fibroblasts, indicating impaired fission of these organelles. In conclusion, we described a recessive disease caused by DNM1L mutations, with a clinical phenotype resembling mitochondrial disorders but without any biochemical features typical of these syndromes (lactic acidosis, respiratory chain complex deficiency) or indicating a peroxisomal disorder.

AB - Mitochondria are highly dynamic organelles, undergoing continuous fission and fusion, and mitochondrial dynamics is important for several cellular functions. DNM1L is the most important mediator of mitochondrial fission, with a role also in peroxisome division. Few reports of patients with genetic defects in DNM1L have been published, most of them describing de novo dominant mutations. We identified compound heterozygous DNM1L variants in two brothers presenting with an infantile slowly progressive neurological impairment. One variant was a frame-shift mutation, the other was a missense change, the pathogenicity of which was validated in a yeast model. Fluorescence microscopy revealed abnormally elongated mitochondria and aberrant peroxisomes in mutant fibroblasts, indicating impaired fission of these organelles. In conclusion, we described a recessive disease caused by DNM1L mutations, with a clinical phenotype resembling mitochondrial disorders but without any biochemical features typical of these syndromes (lactic acidosis, respiratory chain complex deficiency) or indicating a peroxisomal disorder.

KW - DNM1L

KW - mitochondrial disorders

KW - mitochondrial dynamics

KW - mitochondrial fission

KW - peroxisome

UR - http://www.scopus.com/inward/record.url?scp=84982202456&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84982202456&partnerID=8YFLogxK

U2 - 10.1002/humu.23033

DO - 10.1002/humu.23033

M3 - Article

C2 - 27328748

AN - SCOPUS:84982202456

VL - 37

SP - 898

EP - 903

JO - Human Mutation

JF - Human Mutation

SN - 1059-7794

IS - 9

ER -