Clinical, genetic, epidemiologic, evolutionary, and functional delineation of TSPEAR-related autosomal recessive ectodermal dysplasia 14

The Genomics England Research Consortium; Solve-RD consortium; Siddharth Banka

doi:10.1016/j.xhgg.2023.100186

Clinical, genetic, epidemiologic, evolutionary, and functional delineation of TSPEAR-related autosomal recessive ectodermal dysplasia 14

The Genomics England Research Consortium, Solve-RD consortium, Siddharth Banka^*

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

11 Citations (Scopus)

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Abstract

TSPEAR variants cause autosomal recessive ectodermal dysplasia (ARED) 14. The function of TSPEAR is unknown. The clinical features, the mutation spectrum, and the underlying mechanisms of ARED14 are poorly understood. Combining data from new and previously published individuals established that ARED14 is primarily characterized by dental anomalies such as conical tooth cusps and hypodontia, like those seen in individuals with WNT10A-related odontoonychodermal dysplasia. AlphaFold-predicted structure-based analysis showed that most of the pathogenic TSPEAR missense variants likely destabilize the β-propeller of the protein. Analysis of 100000 Genomes Project (100KGP) data revealed multiple founder TSPEAR variants across different populations. Mutational and recombination clock analyses demonstrated that non-Finnish European founder variants likely originated around the end of the last ice age, a period of major climatic transition. Analysis of gnomAD data showed that the non-Finnish European population TSPEAR gene-carrier rate is ∼1/140, making it one of the commonest AREDs. Phylogenetic and AlphaFold structural analyses showed that TSPEAR is an ortholog of drosophila Closca, an extracellular matrix-dependent signaling regulator. We, therefore, hypothesized that TSPEAR could have a role in enamel knot, a structure that coordinates patterning of developing tooth cusps. Analysis of mouse single-cell RNA sequencing (scRNA-seq) data revealed highly restricted expression of Tspear in clusters representing enamel knots. A tspeara^−/−;tspearb^−/− double-knockout zebrafish model recapitulated the clinical features of ARED14 and fin regeneration abnormalities of wnt10a knockout fish, thus suggesting interaction between tspear and wnt10a. In summary, we provide insights into the role of TSPEAR in ectodermal development and the evolutionary history, epidemiology, mechanisms, and consequences of its loss of function variants.

Original language	English
Article number	100186
Number of pages	19
Journal	Human Genetics and Genomics Advances
Volume	4
Issue number	2
DOIs	https://doi.org/10.1016/j.xhgg.2023.100186
Publication status	Published - 13 Apr 2023

Bibliographical note

Funding Information:
This research was made possible through access to the data and findings generated by the 100KGP. The 100KGP is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100KGP is funded by the National Institute for Health Research and NHS England . The Wellcome Trust , Cancer Research UK , and the Medical Research Council have also funded research infrastructure. The 100KGP uses data provided by patients and collected by the National Health Service as part of their care and support. This study makes use of data generated by the DECIPHER community. A full list of centers who contributed to the generation of the data is available from https://deciphergenomics.org/about/stats and via email from [email protected] . Funding for the DECIPHER project was provided by Wellcome . A.J. and S.B. acknowledge the support of Solve-RD. The Solve-RD project has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement no. 779257 .

Funding Information:
This research was made possible through access to the data and findings generated by the 100KGP. The 100KGP is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100KGP is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK, and the Medical Research Council have also funded research infrastructure. The 100KGP uses data provided by patients and collected by the National Health Service as part of their care and support. This study makes use of data generated by the DECIPHER community. A full list of centers who contributed to the generation of the data is available from https://deciphergenomics.org/about/stats and via email from [email protected]. Funding for the DECIPHER project was provided by Wellcome. A.J. and S.B. acknowledge the support of Solve-RD. The Solve-RD project has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement no. 779257. The authors declare no competing interests.

Publisher Copyright:
© 2023 The Author(s)

Keywords

Autosomal recessive ectodermal dysplasia type 14
Closca
Conical teeth
Ectodermal dysplasia
Enamel knot
Extracellular matrix dependant signalling
Hypodontia
TSPEAR
WNT10A
zebrafish fin regeneration

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@article{7fa9a92a90e04e26b0e2de05ba1c6a11,

title = "Clinical, genetic, epidemiologic, evolutionary, and functional delineation of TSPEAR-related autosomal recessive ectodermal dysplasia 14",

abstract = "TSPEAR variants cause autosomal recessive ectodermal dysplasia (ARED) 14. The function of TSPEAR is unknown. The clinical features, the mutation spectrum, and the underlying mechanisms of ARED14 are poorly understood. Combining data from new and previously published individuals established that ARED14 is primarily characterized by dental anomalies such as conical tooth cusps and hypodontia, like those seen in individuals with WNT10A-related odontoonychodermal dysplasia. AlphaFold-predicted structure-based analysis showed that most of the pathogenic TSPEAR missense variants likely destabilize the β-propeller of the protein. Analysis of 100000 Genomes Project (100KGP) data revealed multiple founder TSPEAR variants across different populations. Mutational and recombination clock analyses demonstrated that non-Finnish European founder variants likely originated around the end of the last ice age, a period of major climatic transition. Analysis of gnomAD data showed that the non-Finnish European population TSPEAR gene-carrier rate is ∼1/140, making it one of the commonest AREDs. Phylogenetic and AlphaFold structural analyses showed that TSPEAR is an ortholog of drosophila Closca, an extracellular matrix-dependent signaling regulator. We, therefore, hypothesized that TSPEAR could have a role in enamel knot, a structure that coordinates patterning of developing tooth cusps. Analysis of mouse single-cell RNA sequencing (scRNA-seq) data revealed highly restricted expression of Tspear in clusters representing enamel knots. A tspeara−/−;tspearb−/− double-knockout zebrafish model recapitulated the clinical features of ARED14 and fin regeneration abnormalities of wnt10a knockout fish, thus suggesting interaction between tspear and wnt10a. In summary, we provide insights into the role of TSPEAR in ectodermal development and the evolutionary history, epidemiology, mechanisms, and consequences of its loss of function variants.",

keywords = "Autosomal recessive ectodermal dysplasia type 14, Closca, Conical teeth, Ectodermal dysplasia, Enamel knot, Extracellular matrix dependant signalling, Hypodontia, TSPEAR, WNT10A, zebrafish fin regeneration",

author = "\{The Genomics England Research Consortium\} and \{Solve-RD consortium\} and Adam Jackson and Lin, \{Sheng Jia\} and Jones, \{Elizabeth A.\} and Chandler, \{Kate E.\} and David Orr and Celia Moss and Zahra Haider and Gavin Ryan and Simon Holden and Mike Harrison and Nigel Burrows and Mary Loveless and Cassidy Petree and Helen Stewart and Karen Low and Deirdre Donnelly and Simon Lovell and Konstantina Drosou and Ambrose, \{J. C.\} and P. Arumugam and R. Bevers and M. Bleda and F. Boardman-Pretty and H. Brittain and Caulfield, \{M. J.\} and Chan, \{G. C.\} and A. Giess and A. Hamblin and Hubbard, \{T. J.P.\} and D. Kasperaviciute and Siddharth Banka",

note = "Funding Information: This research was made possible through access to the data and findings generated by the 100KGP. The 100KGP is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100KGP is funded by the National Institute for Health Research and NHS England . The Wellcome Trust , Cancer Research UK , and the Medical Research Council have also funded research infrastructure. The 100KGP uses data provided by patients and collected by the National Health Service as part of their care and support. This study makes use of data generated by the DECIPHER community. A full list of centers who contributed to the generation of the data is available from https://deciphergenomics.org/about/stats and via email from [email protected] . Funding for the DECIPHER project was provided by Wellcome . A.J. and S.B. acknowledge the support of Solve-RD. The Solve-RD project has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement no. 779257 . Funding Information: This research was made possible through access to the data and findings generated by the 100KGP. The 100KGP is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100KGP is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK, and the Medical Research Council have also funded research infrastructure. The 100KGP uses data provided by patients and collected by the National Health Service as part of their care and support. This study makes use of data generated by the DECIPHER community. A full list of centers who contributed to the generation of the data is available from https://deciphergenomics.org/about/stats and via email from [email protected]. Funding for the DECIPHER project was provided by Wellcome. A.J. and S.B. acknowledge the support of Solve-RD. The Solve-RD project has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement no. 779257. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2023 The Author(s)",

year = "2023",

month = apr,

day = "13",

doi = "10.1016/j.xhgg.2023.100186",

language = "English",

volume = "4",

journal = "Human Genetics and Genomics Advances",

issn = "2666-2477",

publisher = "Elsevier Inc.",

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Clinical, genetic, epidemiologic, evolutionary, and functional delineation of TSPEAR-related autosomal recessive ectodermal dysplasia 14. / The Genomics England Research Consortium; Solve-RD consortium; Banka, Siddharth.
In: Human Genetics and Genomics Advances, Vol. 4, No. 2, 100186, 13.04.2023.

Research output: Contribution to journal › Article (Academic Journal) › peer-review

TY - JOUR

T1 - Clinical, genetic, epidemiologic, evolutionary, and functional delineation of TSPEAR-related autosomal recessive ectodermal dysplasia 14

AU - The Genomics England Research Consortium

AU - Solve-RD consortium

AU - Jackson, Adam

AU - Lin, Sheng Jia

AU - Jones, Elizabeth A.

AU - Chandler, Kate E.

AU - Orr, David

AU - Moss, Celia

AU - Haider, Zahra

AU - Ryan, Gavin

AU - Holden, Simon

AU - Harrison, Mike

AU - Burrows, Nigel

AU - Loveless, Mary

AU - Petree, Cassidy

AU - Stewart, Helen

AU - Low, Karen

AU - Donnelly, Deirdre

AU - Lovell, Simon

AU - Drosou, Konstantina

AU - Ambrose, J. C.

AU - Arumugam, P.

AU - Bevers, R.

AU - Bleda, M.

AU - Boardman-Pretty, F.

AU - Brittain, H.

AU - Caulfield, M. J.

AU - Chan, G. C.

AU - Giess, A.

AU - Hamblin, A.

AU - Hubbard, T. J.P.

AU - Kasperaviciute, D.

AU - Banka, Siddharth

N1 - Funding Information: This research was made possible through access to the data and findings generated by the 100KGP. The 100KGP is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100KGP is funded by the National Institute for Health Research and NHS England . The Wellcome Trust , Cancer Research UK , and the Medical Research Council have also funded research infrastructure. The 100KGP uses data provided by patients and collected by the National Health Service as part of their care and support. This study makes use of data generated by the DECIPHER community. A full list of centers who contributed to the generation of the data is available from https://deciphergenomics.org/about/stats and via email from [email protected] . Funding for the DECIPHER project was provided by Wellcome . A.J. and S.B. acknowledge the support of Solve-RD. The Solve-RD project has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement no. 779257 . Funding Information: This research was made possible through access to the data and findings generated by the 100KGP. The 100KGP is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100KGP is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK, and the Medical Research Council have also funded research infrastructure. The 100KGP uses data provided by patients and collected by the National Health Service as part of their care and support. This study makes use of data generated by the DECIPHER community. A full list of centers who contributed to the generation of the data is available from https://deciphergenomics.org/about/stats and via email from [email protected]. Funding for the DECIPHER project was provided by Wellcome. A.J. and S.B. acknowledge the support of Solve-RD. The Solve-RD project has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement no. 779257. The authors declare no competing interests. Publisher Copyright: © 2023 The Author(s)

PY - 2023/4/13

Y1 - 2023/4/13

N2 - TSPEAR variants cause autosomal recessive ectodermal dysplasia (ARED) 14. The function of TSPEAR is unknown. The clinical features, the mutation spectrum, and the underlying mechanisms of ARED14 are poorly understood. Combining data from new and previously published individuals established that ARED14 is primarily characterized by dental anomalies such as conical tooth cusps and hypodontia, like those seen in individuals with WNT10A-related odontoonychodermal dysplasia. AlphaFold-predicted structure-based analysis showed that most of the pathogenic TSPEAR missense variants likely destabilize the β-propeller of the protein. Analysis of 100000 Genomes Project (100KGP) data revealed multiple founder TSPEAR variants across different populations. Mutational and recombination clock analyses demonstrated that non-Finnish European founder variants likely originated around the end of the last ice age, a period of major climatic transition. Analysis of gnomAD data showed that the non-Finnish European population TSPEAR gene-carrier rate is ∼1/140, making it one of the commonest AREDs. Phylogenetic and AlphaFold structural analyses showed that TSPEAR is an ortholog of drosophila Closca, an extracellular matrix-dependent signaling regulator. We, therefore, hypothesized that TSPEAR could have a role in enamel knot, a structure that coordinates patterning of developing tooth cusps. Analysis of mouse single-cell RNA sequencing (scRNA-seq) data revealed highly restricted expression of Tspear in clusters representing enamel knots. A tspeara−/−;tspearb−/− double-knockout zebrafish model recapitulated the clinical features of ARED14 and fin regeneration abnormalities of wnt10a knockout fish, thus suggesting interaction between tspear and wnt10a. In summary, we provide insights into the role of TSPEAR in ectodermal development and the evolutionary history, epidemiology, mechanisms, and consequences of its loss of function variants.

AB - TSPEAR variants cause autosomal recessive ectodermal dysplasia (ARED) 14. The function of TSPEAR is unknown. The clinical features, the mutation spectrum, and the underlying mechanisms of ARED14 are poorly understood. Combining data from new and previously published individuals established that ARED14 is primarily characterized by dental anomalies such as conical tooth cusps and hypodontia, like those seen in individuals with WNT10A-related odontoonychodermal dysplasia. AlphaFold-predicted structure-based analysis showed that most of the pathogenic TSPEAR missense variants likely destabilize the β-propeller of the protein. Analysis of 100000 Genomes Project (100KGP) data revealed multiple founder TSPEAR variants across different populations. Mutational and recombination clock analyses demonstrated that non-Finnish European founder variants likely originated around the end of the last ice age, a period of major climatic transition. Analysis of gnomAD data showed that the non-Finnish European population TSPEAR gene-carrier rate is ∼1/140, making it one of the commonest AREDs. Phylogenetic and AlphaFold structural analyses showed that TSPEAR is an ortholog of drosophila Closca, an extracellular matrix-dependent signaling regulator. We, therefore, hypothesized that TSPEAR could have a role in enamel knot, a structure that coordinates patterning of developing tooth cusps. Analysis of mouse single-cell RNA sequencing (scRNA-seq) data revealed highly restricted expression of Tspear in clusters representing enamel knots. A tspeara−/−;tspearb−/− double-knockout zebrafish model recapitulated the clinical features of ARED14 and fin regeneration abnormalities of wnt10a knockout fish, thus suggesting interaction between tspear and wnt10a. In summary, we provide insights into the role of TSPEAR in ectodermal development and the evolutionary history, epidemiology, mechanisms, and consequences of its loss of function variants.

KW - Autosomal recessive ectodermal dysplasia type 14

KW - Closca

KW - Conical teeth

KW - Ectodermal dysplasia

KW - Enamel knot

KW - Extracellular matrix dependant signalling

KW - Hypodontia

KW - TSPEAR

KW - WNT10A

KW - zebrafish fin regeneration

UR - https://www.scopus.com/pages/publications/85150337683

U2 - 10.1016/j.xhgg.2023.100186

DO - 10.1016/j.xhgg.2023.100186

M3 - Article (Academic Journal)

C2 - 37009414

AN - SCOPUS:85150337683

SN - 2666-2477

VL - 4

JO - Human Genetics and Genomics Advances

JF - Human Genetics and Genomics Advances

IS - 2

M1 - 100186

ER -

Clinical, genetic, epidemiologic, evolutionary, and functional delineation of TSPEAR-related autosomal recessive ectodermal dysplasia 14

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