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

Kimberly M. Reid; Robert Spaull; Smrithi Salian; Katy Barwick; Esther Meyer; Juan Zhen; Hiromi Hirata; Diba Sheipouri; Hind Benkerroum; Kathleen M. Gorman; Apostolos Papandreou; Michael A. Simpson; Yoshinobu Hirano; Irene Farabella; Maya Topf; Detelina Grozeva; Keren Carss; Martin Smith; Hardev Pall; Peter Lunt; Susanna De Gressi; Erik-Jan Kamsteeg; Tobias B Haack; Lucinda Carr; Rita Guerreiro; Jose Bras; Eamonn R. Maher; Robert J. Vandenberg; F. Lucy Raymond; Wui K Chong; Sniya Sudhakar; Kshitij Mankad; Maarten E Reith; Philippe M. Campeau; Robert J. Harvey; Manju A. Kurian

doi:10.1002/mds.29147

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

Kimberly M. Reid, Robert Spaull, Smrithi Salian, Katy Barwick, Esther Meyer, Juan Zhen, Hiromi Hirata, Diba Sheipouri, Hind Benkerroum, Kathleen M. Gorman, Apostolos Papandreou, Michael A. Simpson, Yoshinobu Hirano, Irene Farabella, Maya Topf, Detelina Grozeva, Keren Carss, Martin Smith, Hardev Pall, Peter LuntSusanna De Gressi, Erik-Jan Kamsteeg, Tobias B Haack, Lucinda Carr, Rita Guerreiro, Jose Bras, Eamonn R. Maher, Robert J. Vandenberg, F. Lucy Raymond, Wui K Chong, Sniya Sudhakar, Kshitij Mankad, Maarten E Reith, Philippe M. Campeau, Robert J. Harvey, Manju A. Kurian

Aston Medical School

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	2139-2146
Number of pages	8
Journal	Movement Disorders
Volume	37
Issue number	10
Early online date	25 Jul 2022
DOIs	https://doi.org/10.1002/mds.29147
Publication status	Published - Oct 2022

Bibliographical note

Copyright © 2022, The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Keywords

Animals
Dystonia/diagnosis
Dystonic Disorders/genetics
Movement Disorders/genetics
Neurodevelopmental Disorders/genetics
Proline
RNA
Zebrafish/genetics

Access to Document

10.1002/mds.29147Licence: CC BY 4.0

Movement Disorders - 2022 - Reid - MED27 SLC6A7 and MPPE1 Variants in a Complex Neurodevelopmental Disorder with Severe
Copyright © 2022, The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Final published version, 6.35 MBLicence: CC BY 4.0

Cite this

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., ... Kurian, M. A. (2022). MED27, SLC6A7, and MPPE1 Variants in a Complex Neurodevelopmental Disorder with Severe Dystonia. Movement Disorders, 37(10), 2139-2146. https://doi.org/10.1002/mds.29147

@article{befa39c527d54f80bf6d1247da617cd8,

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. {\textcopyright} 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.",

keywords = "Animals, Dystonia/diagnosis, Dystonic Disorders/genetics, Movement Disorders/genetics, Neurodevelopmental Disorders/genetics, Proline, RNA, Zebrafish/genetics",

author = "Reid, {Kimberly M.} and Robert Spaull and Smrithi Salian and Katy Barwick and Esther Meyer and Juan Zhen and Hiromi Hirata and Diba Sheipouri and Hind Benkerroum and Gorman, {Kathleen M.} and Apostolos Papandreou and Simpson, {Michael A.} and Yoshinobu Hirano and Irene Farabella and Maya Topf and Detelina Grozeva and Keren Carss and Martin Smith and Hardev Pall and Peter Lunt and {De Gressi}, Susanna and Erik-Jan Kamsteeg and Haack, {Tobias B} and Lucinda Carr and Rita Guerreiro and Jose Bras and Maher, {Eamonn R.} and Vandenberg, {Robert J.} and Raymond, {F. Lucy} and Chong, {Wui K} and Sniya Sudhakar and Kshitij Mankad and Reith, {Maarten E} and Campeau, {Philippe M.} and Harvey, {Robert J.} and Kurian, {Manju A.}",

note = "Copyright {\textcopyright} 2022, The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.",

year = "2022",

month = oct,

doi = "10.1002/mds.29147",

language = "English",

volume = "37",

pages = "2139--2146",

journal = "Movement Disorders",

issn = "0885-3185",

publisher = "Wiley",

number = "10",

}

Reid, KM, Spaull, R, Salian, S, Barwick, K, Meyer, E, Zhen, J, Hirata, H, Sheipouri, D, Benkerroum, H, Gorman, KM, Papandreou, A, Simpson, MA, Hirano, Y, Farabella, I, Topf, M, Grozeva, D, Carss, K, Smith, M, Pall, H, Lunt, P, De Gressi, S, Kamsteeg, E-J, Haack, TB, Carr, L, Guerreiro, R, Bras, J, Maher, ER, Vandenberg, RJ, Raymond, FL, Chong, WK, Sudhakar, S, Mankad, K, Reith, ME, Campeau, PM, Harvey, RJ & Kurian, MA 2022, 'MED27, SLC6A7, and MPPE1 Variants in a Complex Neurodevelopmental Disorder with Severe Dystonia', Movement Disorders, vol. 37, no. 10, pp. 2139-2146. https://doi.org/10.1002/mds.29147

TY - JOUR

T1 - MED27, SLC6A7, and MPPE1 Variants in a Complex Neurodevelopmental Disorder with Severe Dystonia

AU - Reid, Kimberly M.

AU - Spaull, Robert

AU - Salian, Smrithi

AU - Barwick, Katy

AU - Meyer, Esther

AU - Zhen, Juan

AU - Hirata, Hiromi

AU - Sheipouri, Diba

AU - Benkerroum, Hind

AU - Gorman, Kathleen M.

AU - Papandreou, Apostolos

AU - Simpson, Michael A.

AU - Hirano, Yoshinobu

AU - Farabella, Irene

AU - Topf, Maya

AU - Grozeva, Detelina

AU - Carss, Keren

AU - Smith, Martin

AU - Pall, Hardev

AU - Lunt, Peter

AU - De Gressi, Susanna

AU - Kamsteeg, Erik-Jan

AU - Haack, Tobias B

AU - Carr, Lucinda

AU - Guerreiro, Rita

AU - Bras, Jose

AU - Maher, Eamonn R.

AU - Vandenberg, Robert J.

AU - Raymond, F. Lucy

AU - Chong, Wui K

AU - Sudhakar, Sniya

AU - Mankad, Kshitij

AU - Reith, Maarten E

AU - Campeau, Philippe M.

AU - Harvey, Robert J.

AU - Kurian, Manju A.

N1 - Copyright © 2022, The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

PY - 2022/10

Y1 - 2022/10

N2 - 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.

AB - 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.

KW - Animals

KW - Dystonia/diagnosis

KW - Dystonic Disorders/genetics

KW - Movement Disorders/genetics

KW - Neurodevelopmental Disorders/genetics

KW - Proline

KW - RNA

KW - Zebrafish/genetics

UR - https://movementdisorders.onlinelibrary.wiley.com/doi/10.1002/mds.29147

U2 - 10.1002/mds.29147

DO - 10.1002/mds.29147

M3 - Article

C2 - 35876425

SN - 0885-3185

VL - 37

SP - 2139

EP - 2146

JO - Movement Disorders

JF - Movement Disorders

IS - 10

ER -

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

Abstract

Bibliographical note

Keywords

Access to Document

Other files and links

Fingerprint

Cite this