Analysis of motor dysfunction in Down Syndrome reveals motor neuron degeneration.
Down Syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and results in a spectrum of phenotypes including learning and memory deficits, and motor dysfunction. It has been hypothesized that an additional copy of a few Hsa21 dosage-sensitive genes causes these phenotypes, but this has been ch...
Main Authors: | , , , , , , , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Public Library of Science (PLoS)
2018-05-01
|
Series: | PLoS Genetics |
Online Access: | https://doi.org/10.1371/journal.pgen.1007383 |
id |
doaj-cf34bed66d614aab8625e9cbd15f2434 |
---|---|
record_format |
Article |
spelling |
doaj-cf34bed66d614aab8625e9cbd15f24342021-04-21T14:32:57ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042018-05-01145e100738310.1371/journal.pgen.1007383Analysis of motor dysfunction in Down Syndrome reveals motor neuron degeneration.Sheona Watson-ScalesBernadett KalmarEva Lana-ElolaDorota GibbinsFederica La RussaFrances WisemanMatthew WilliamsonRachele SacconAmy SlenderAnna OlerinyovaRadma MahmoodEmma NyeHeather CaterSara WellsY Eugene YuDavid L H BennettLinda GreensmithElizabeth M C FisherVictor L J TybulewiczDown Syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and results in a spectrum of phenotypes including learning and memory deficits, and motor dysfunction. It has been hypothesized that an additional copy of a few Hsa21 dosage-sensitive genes causes these phenotypes, but this has been challenged by observations that aneuploidy can cause phenotypes by the mass action of large numbers of genes, with undetectable contributions from individual sequences. The motor abnormalities in DS are relatively understudied-the identity of causative dosage-sensitive genes and the mechanism underpinning the phenotypes are unknown. Using a panel of mouse strains with duplications of regions of mouse chromosomes orthologous to Hsa21 we show that increased dosage of small numbers of genes causes locomotor dysfunction and, moreover, that the Dyrk1a gene is required in three copies to cause the phenotype. Furthermore, we show for the first time a new DS phenotype: loss of motor neurons both in mouse models and, importantly, in humans with DS, that may contribute to locomotor dysfunction.https://doi.org/10.1371/journal.pgen.1007383 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Sheona Watson-Scales Bernadett Kalmar Eva Lana-Elola Dorota Gibbins Federica La Russa Frances Wiseman Matthew Williamson Rachele Saccon Amy Slender Anna Olerinyova Radma Mahmood Emma Nye Heather Cater Sara Wells Y Eugene Yu David L H Bennett Linda Greensmith Elizabeth M C Fisher Victor L J Tybulewicz |
spellingShingle |
Sheona Watson-Scales Bernadett Kalmar Eva Lana-Elola Dorota Gibbins Federica La Russa Frances Wiseman Matthew Williamson Rachele Saccon Amy Slender Anna Olerinyova Radma Mahmood Emma Nye Heather Cater Sara Wells Y Eugene Yu David L H Bennett Linda Greensmith Elizabeth M C Fisher Victor L J Tybulewicz Analysis of motor dysfunction in Down Syndrome reveals motor neuron degeneration. PLoS Genetics |
author_facet |
Sheona Watson-Scales Bernadett Kalmar Eva Lana-Elola Dorota Gibbins Federica La Russa Frances Wiseman Matthew Williamson Rachele Saccon Amy Slender Anna Olerinyova Radma Mahmood Emma Nye Heather Cater Sara Wells Y Eugene Yu David L H Bennett Linda Greensmith Elizabeth M C Fisher Victor L J Tybulewicz |
author_sort |
Sheona Watson-Scales |
title |
Analysis of motor dysfunction in Down Syndrome reveals motor neuron degeneration. |
title_short |
Analysis of motor dysfunction in Down Syndrome reveals motor neuron degeneration. |
title_full |
Analysis of motor dysfunction in Down Syndrome reveals motor neuron degeneration. |
title_fullStr |
Analysis of motor dysfunction in Down Syndrome reveals motor neuron degeneration. |
title_full_unstemmed |
Analysis of motor dysfunction in Down Syndrome reveals motor neuron degeneration. |
title_sort |
analysis of motor dysfunction in down syndrome reveals motor neuron degeneration. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Genetics |
issn |
1553-7390 1553-7404 |
publishDate |
2018-05-01 |
description |
Down Syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and results in a spectrum of phenotypes including learning and memory deficits, and motor dysfunction. It has been hypothesized that an additional copy of a few Hsa21 dosage-sensitive genes causes these phenotypes, but this has been challenged by observations that aneuploidy can cause phenotypes by the mass action of large numbers of genes, with undetectable contributions from individual sequences. The motor abnormalities in DS are relatively understudied-the identity of causative dosage-sensitive genes and the mechanism underpinning the phenotypes are unknown. Using a panel of mouse strains with duplications of regions of mouse chromosomes orthologous to Hsa21 we show that increased dosage of small numbers of genes causes locomotor dysfunction and, moreover, that the Dyrk1a gene is required in three copies to cause the phenotype. Furthermore, we show for the first time a new DS phenotype: loss of motor neurons both in mouse models and, importantly, in humans with DS, that may contribute to locomotor dysfunction. |
url |
https://doi.org/10.1371/journal.pgen.1007383 |
work_keys_str_mv |
AT sheonawatsonscales analysisofmotordysfunctionindownsyndromerevealsmotorneurondegeneration AT bernadettkalmar analysisofmotordysfunctionindownsyndromerevealsmotorneurondegeneration AT evalanaelola analysisofmotordysfunctionindownsyndromerevealsmotorneurondegeneration AT dorotagibbins analysisofmotordysfunctionindownsyndromerevealsmotorneurondegeneration AT federicalarussa analysisofmotordysfunctionindownsyndromerevealsmotorneurondegeneration AT franceswiseman analysisofmotordysfunctionindownsyndromerevealsmotorneurondegeneration AT matthewwilliamson analysisofmotordysfunctionindownsyndromerevealsmotorneurondegeneration AT rachelesaccon analysisofmotordysfunctionindownsyndromerevealsmotorneurondegeneration AT amyslender analysisofmotordysfunctionindownsyndromerevealsmotorneurondegeneration AT annaolerinyova analysisofmotordysfunctionindownsyndromerevealsmotorneurondegeneration AT radmamahmood analysisofmotordysfunctionindownsyndromerevealsmotorneurondegeneration AT emmanye analysisofmotordysfunctionindownsyndromerevealsmotorneurondegeneration AT heathercater analysisofmotordysfunctionindownsyndromerevealsmotorneurondegeneration AT sarawells analysisofmotordysfunctionindownsyndromerevealsmotorneurondegeneration AT yeugeneyu analysisofmotordysfunctionindownsyndromerevealsmotorneurondegeneration AT davidlhbennett analysisofmotordysfunctionindownsyndromerevealsmotorneurondegeneration AT lindagreensmith analysisofmotordysfunctionindownsyndromerevealsmotorneurondegeneration AT elizabethmcfisher analysisofmotordysfunctionindownsyndromerevealsmotorneurondegeneration AT victorljtybulewicz analysisofmotordysfunctionindownsyndromerevealsmotorneurondegeneration |
_version_ |
1714668327070072832 |