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Final Exon Frameshift Biallelic PTPN23 Variants Are Associated with Microcephalic Complex Hereditary Spastic Paraplegia

The hereditary spastic paraplegias (HSPs) are a large clinically heterogeneous group of genetic disorders classified as ‘pure’ when the cardinal feature of progressive lower limb spasticity and weakness occurs in isolation and ‘complex’ when associated with other clinical signs. Here, we identify a...

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Autores principales: Khalaf-Nazzal, Reham, Fasham, James, Ubeyratna, Nishanka, Evans, David J., Leslie, Joseph S., Warner, Thomas T., Al-Hijawi, Fida’, Alshaer, Shurouq, Baker, Wisam, Turnpenny, Peter D., Baple, Emma L., Crosby, Andrew H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151426/
https://www.ncbi.nlm.nih.gov/pubmed/34064836
http://dx.doi.org/10.3390/brainsci11050614
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author Khalaf-Nazzal, Reham
Fasham, James
Ubeyratna, Nishanka
Evans, David J.
Leslie, Joseph S.
Warner, Thomas T.
Al-Hijawi, Fida’
Alshaer, Shurouq
Baker, Wisam
Turnpenny, Peter D.
Baple, Emma L.
Crosby, Andrew H.
author_facet Khalaf-Nazzal, Reham
Fasham, James
Ubeyratna, Nishanka
Evans, David J.
Leslie, Joseph S.
Warner, Thomas T.
Al-Hijawi, Fida’
Alshaer, Shurouq
Baker, Wisam
Turnpenny, Peter D.
Baple, Emma L.
Crosby, Andrew H.
author_sort Khalaf-Nazzal, Reham
collection PubMed
description The hereditary spastic paraplegias (HSPs) are a large clinically heterogeneous group of genetic disorders classified as ‘pure’ when the cardinal feature of progressive lower limb spasticity and weakness occurs in isolation and ‘complex’ when associated with other clinical signs. Here, we identify a homozygous frameshift alteration occurring in the last coding exon of the protein tyrosine phosphatase type 23 (PTPN23) gene in an extended Palestinian family associated with autosomal recessive complex HSP. PTPN23 encodes a catalytically inert non-receptor protein tyrosine phosphatase that has been proposed to interact with the endosomal sorting complex required for transport (ESCRT) complex, involved in the sorting of ubiquitinated cargos for fusion with lysosomes. In view of our data, we reviewed previously published candidate pathogenic PTPN23 variants to clarify clinical outcomes associated with pathogenic gene variants. This determined that a number of previously proposed candidate PTPN23 alterations are likely benign and revealed that pathogenic biallelic PTPN23 alterations cause a varied clinical spectrum comprising of complex HSP associated with microcephaly, which may occur without intellectual impairment or involve more severe neurological disease. Together, these findings highlight the importance of the inclusion of the PTPN23 gene on HSP gene testing panels globally.
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spelling pubmed-81514262021-05-27 Final Exon Frameshift Biallelic PTPN23 Variants Are Associated with Microcephalic Complex Hereditary Spastic Paraplegia Khalaf-Nazzal, Reham Fasham, James Ubeyratna, Nishanka Evans, David J. Leslie, Joseph S. Warner, Thomas T. Al-Hijawi, Fida’ Alshaer, Shurouq Baker, Wisam Turnpenny, Peter D. Baple, Emma L. Crosby, Andrew H. Brain Sci Article The hereditary spastic paraplegias (HSPs) are a large clinically heterogeneous group of genetic disorders classified as ‘pure’ when the cardinal feature of progressive lower limb spasticity and weakness occurs in isolation and ‘complex’ when associated with other clinical signs. Here, we identify a homozygous frameshift alteration occurring in the last coding exon of the protein tyrosine phosphatase type 23 (PTPN23) gene in an extended Palestinian family associated with autosomal recessive complex HSP. PTPN23 encodes a catalytically inert non-receptor protein tyrosine phosphatase that has been proposed to interact with the endosomal sorting complex required for transport (ESCRT) complex, involved in the sorting of ubiquitinated cargos for fusion with lysosomes. In view of our data, we reviewed previously published candidate pathogenic PTPN23 variants to clarify clinical outcomes associated with pathogenic gene variants. This determined that a number of previously proposed candidate PTPN23 alterations are likely benign and revealed that pathogenic biallelic PTPN23 alterations cause a varied clinical spectrum comprising of complex HSP associated with microcephaly, which may occur without intellectual impairment or involve more severe neurological disease. Together, these findings highlight the importance of the inclusion of the PTPN23 gene on HSP gene testing panels globally. MDPI 2021-05-11 /pmc/articles/PMC8151426/ /pubmed/34064836 http://dx.doi.org/10.3390/brainsci11050614 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Khalaf-Nazzal, Reham
Fasham, James
Ubeyratna, Nishanka
Evans, David J.
Leslie, Joseph S.
Warner, Thomas T.
Al-Hijawi, Fida’
Alshaer, Shurouq
Baker, Wisam
Turnpenny, Peter D.
Baple, Emma L.
Crosby, Andrew H.
Final Exon Frameshift Biallelic PTPN23 Variants Are Associated with Microcephalic Complex Hereditary Spastic Paraplegia
title Final Exon Frameshift Biallelic PTPN23 Variants Are Associated with Microcephalic Complex Hereditary Spastic Paraplegia
title_full Final Exon Frameshift Biallelic PTPN23 Variants Are Associated with Microcephalic Complex Hereditary Spastic Paraplegia
title_fullStr Final Exon Frameshift Biallelic PTPN23 Variants Are Associated with Microcephalic Complex Hereditary Spastic Paraplegia
title_full_unstemmed Final Exon Frameshift Biallelic PTPN23 Variants Are Associated with Microcephalic Complex Hereditary Spastic Paraplegia
title_short Final Exon Frameshift Biallelic PTPN23 Variants Are Associated with Microcephalic Complex Hereditary Spastic Paraplegia
title_sort final exon frameshift biallelic ptpn23 variants are associated with microcephalic complex hereditary spastic paraplegia
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151426/
https://www.ncbi.nlm.nih.gov/pubmed/34064836
http://dx.doi.org/10.3390/brainsci11050614
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