MED27, SLC6A7, and MPPE1 variants in a complex neurodevelopmental disorder with severe dystonia Journal Article
| 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. |
| Article Title: | MED27, SLC6A7, and MPPE1 variants in a complex neurodevelopmental disorder with severe dystonia |
| Abstract: | Background: 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. Objective: 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. Methods: Candidate genes identified by autozygosity mapping and whole-exome sequencing were characterized using cellular and vertebrate model systems. Results: 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. Conclusions: 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. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. |
| Keywords: | child; clinical article; human tissue; school child; single nucleotide polymorphism; genetics; case report; neuroimaging; nuclear magnetic resonance imaging; genetic analysis; phenotype; animal; animals; gene; disease association; gene overexpression; carboxy terminal sequence; genetic variation; in vitro study; rna; endoplasmic reticulum; messenger rna; fibroblast; mental disease; cataract; sibling; motor dysfunction; epilepsy; zebra fish; zebrafish; corpus striatum; proline; biotinylation; motoneuron; genotyping; movement disorders; dystonia; human; male; female; article; chorea; developmental delay; whole exome sequencing; motor development; morpholino oligonucleotide; hek293t cell line; golgi membrane; neurodevelopmental disorders; med27; mppe1; slc6a7; status dystonicus; cadmium 109; cerebellum hypoplasia; generalized dystonia; med27 gene; mppe1 gene; slc6a7 gene; dystonic disorder; dystonic disorders |
| Journal Title: | Movement Disorders |
| Volume: | 37 |
| Issue: | 10 |
| ISSN: | 0885-3185 |
| Publisher: | Wiley Blackwell |
| Date Published: | 2022-10-01 |
| Start Page: | 2139 |
| End Page: | 2146 |
| Language: | English |
| DOI: | 10.1002/mds.29147 |
| PUBMED: | 35876425 |
| PROVIDER: | scopus |
| PMCID: | PMC9796674 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 November 2022 -- Source: Scopus |
