PUBLICATION

MED27, SLC6A7, and MPPE1 Variants in a Complex Neurodevelopmental Disorder with Severe Dystonia

Authors
Reid, K.M., Spaull, R., Salian, S., Barwick, K., Meyer, E., Zhen, J., Hirata, H., Sheipouri, D., Benkerroum, H., Gorman, K.M., Papandreou, A., Simpson, M.A., Hirano, Y., Farabella, I., Topf, M., Grozeva, D., Carss, K., Smith, M., Pall, H., Lunt, P., De Gressi, S., Kamsteeg, E.J., Haack, T.B., Carr, L., Guerreiro, R., Bras, J., Maher, E.R., Scott, R.H., Vandenberg, R.J., Raymond, F.L., Chong, W.K., Sudhakar, S., Mankad, K., Reith, M.E., Campeau, P.M., Harvey, R.J., Kurian, M.A.
ID
ZDB-PUB-220726-27
Date
2022
Source
Movement disorders : official journal of the Movement Disorder Society   37(10): 2139-2146 (Journal)
Registered Authors
Hirata, Hiromi
Keywords
MED27, MPPE1, SLC6A7, dystonia, status dystonicus
MeSH Terms
  • Animals
  • Dystonia*/diagnosis
  • Dystonia*/genetics
  • Zebrafish/genetics
  • Movement Disorders*/genetics
  • Dystonic Disorders*/genetics
  • Proline
  • Neurodevelopmental Disorders*/genetics
  • RNA
(all 9)
PubMed
35876425 Full text @ Mov. Disord.
Abstract
Despite advances in next generation sequencing technologies, the identification of variants of uncertain significance (VUS) can often hinder definitive diagnosis in patients with complex neurodevelopmental disorders.
The objective of this study was to identify and characterize the underlying cause of disease in a family with two children with severe developmental delay associated with generalized dystonia and episodic status dystonicus, chorea, epilepsy, and cataracts.
Candidate genes identified by autozygosity mapping and whole-exome sequencing were characterized using cellular and vertebrate model systems.
Homozygous variants were found in three candidate genes: MED27, SLC6A7, and MPPE1. Although the patients had features of MED27-related disorder, the SLC6A7 and MPPE1 variants were functionally investigated. SLC6A7 variant in vitro overexpression caused decreased proline transport as a result of reduced cell-surface expression, and zebrafish knockdown of slc6a7 exhibited developmental delay and fragile motor neuron morphology that could not be rescued by L-proline transporter-G396S RNA. Lastly, patient fibroblasts displayed reduced cell-surface expression of glycophosphatidylinositol-anchored proteins linked to MPPE1 dysfunction.
We report a family harboring a homozygous MED27 variant with additional loss-of-function SLC6A7 and MPPE1 gene variants, which potentially contribute to a blended phenotype caused by multilocus pathogenic variants. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Genes / Markers
Figures
Figure Gallery (2 images)
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
nig2TgTransgenic Insertion
    1 - 1 of 1
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    Human Disease / Model
    No data available
    Sequence Targeting Reagents
    Target Reagent Reagent Type
    slc6a7MO1-slc6a7MRPHLNO
    1 - 1 of 1
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    Fish
    Antibodies
    No data available
    Orthology
    No data available
    Engineered Foreign Genes
    Marker Marker Type Name
    VenusEFGVenus
    1 - 1 of 1
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    Mapping
    No data available