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

Jackson A(1)(2), Lin SJ(3), Jones EA(1)(2), Chandler KE(2), Orr D(2), Moss C(4), Haider Z(4), Ryan G(5), Holden S(6), Harrison M(7), Burrows N(8), Jones WD(9), Loveless M(3), Petree C(3), Stewart H(10), Low K(11), Donnelly D(12), Lovell S(1), Drosou K(13)(14); Genomics England Research Consortium; Solve-RD consortium; Varshney GK(3), Banka S(1)(2).

Collaborators: Ambrose JC, Arumugam P, Bevers R, Bleda M, Boardman-Pretty F,
Boustred CR, Brittain H, Brown MA, Caulfield MJ, Chan GC, Giess A, Griffin JN,
Hamblin A, Henderson S, Hubbard TJP, Jackson R, Jones LJ, Kasperaviciute D,
Kayikci M, Kousathanas A, Lahnstein L, Lakey A, Leigh SEA, Leong IUS, Lopez FJ,
Maleady-Crowe F, McEntagart M, Minneci F, Mitchell J, Moutsianas L, Mueller M,
Murugaesu N, Need AC, O’Donovan P, Odhams CA, Patch C, Perez-Gil D, Pereira MB,
Pullinger J, Rahim T, Rendon A, Rogers T, Savage K, Sawant K, Scott RH, Siddiq
A, Sieghart A, Smith SC, Sosinsky A, Stuckey A, Tanguy M, Taylor Tavares AL,
Thomas ERA, Thompson SR, Tucci A, Welland MJ, Williams E, Witkowska K, Wood SM,
Zarowiecki M, Riess O, Haack TB, Graessner H, Zurek B, Ellwanger K, Ossowski S,
Demidov G, Sturm M, Schulze-Hentrich JM, Schüle R, Kessler C, Wayand M, Synofzik
M, Wilke C, Traschütz A, Schöls L, Hengel H, Heutink P, Brunner H, Scheffer H,
Hoogerbrugge N, Hoischen A, ‘t Hoen PA, Vissers LE, Gilissen C, Steyaert W,
Sablauskas K, de Voer RM, Kamsteeg EJ, van de Warrenburg B, van Os N, Paske IT,
Janssen E, de Boer E, Steehouwer M, Yaldiz B, Kleefstra T, Brookes AJ, Veal C,
Gibson S, Wadsley M, Mehtarizadeh M, Riaz U, Warren G, Dizjikan FY, Shorter T,
Töpf A, Straub V, Bettolo CM, Specht S, Clayton-Smith J, Banka S, Alexander E,
Jackson A, Faivre L, Thauvin C, Vitobello A, Denommé-Pichon AS, Duffourd Y,
Tisserant E, Bruel AL, Peyron C, Pélissier A, Beltran S, Gut IG, Laurie S,
Piscia D, Matalonga L, Papakonstantinou A, Bullich G, Corvo A, Garcia C,
Fernandez-Callejo M, Hernández C, Picó D, Paramonov I, Lochmüller H, Gumus G,
Bros-Facer V, Rath A, Hanauer M, Olry A, Lagorce D, Havrylenko S, Izem K, Rigour
F, Stevanin G, Durr A, Davoine CS, Guillot-Noel L, Heinzmann A, Coarelli G,
Bonne G, Evangelista T, Allamand V, Nelson I, Ben Yaou R, Metay C, Eymard B,
Cohen E, Atalaia A, Stojkovic T, Macek M Jr, Turnovec M, Thomasová D, Kremliková
RP, Franková V, Havlovicová M, Kremlik V, Parkinson H, Keane T, Spalding D, Senf
A, Robinson P, Danis D, Robert G, Costa A, Patch C, Hanna M, Houlden H, Reilly
M, Vandrovcova J, Muntoni F, Zaharieva I, Sarkozy A, Timmerman V, Baets J, Van
de Vondel L, Beijer D, de Jonghe P, Nigro V, Banfi S, Torella A, Musacchia F,
Piluso G, Ferlini A, Selvatici R, Rossi R, Neri M, Aretz S, Spier I, Sommer AK,
Peters S, Oliveira C, Pelaez JG, Matos AR, José CS, Ferreira M, Gullo I,
Fernandes S, Garrido L, Ferreira P, Carneiro F, Swertz MA, Johansson L, van der
Velde JK, van der Vries G, Neerincx PB, Roelofs-Prins D, Köhler S, Metcalfe A,
Verloes A, Drunat S, Rooryck C, Trimouille A, Castello R, Morleo M, Pinelli M,
Varavallo A, De la Paz MP, Sánchez EB, Martín EL, Delgado BM, Alonso García de
la Rosa FJ, Ciolfi A, Dallapiccola B, Pizzi S, Radio FC, Tartaglia M, Renieri A,
Benetti E, Balicza P, Molnar MJ, Maver A, Peterlin B, Münchau A, Lohmann K,
Herzog R, Pauly M, Macaya A, Marcé-Grau A, Osorio AN, Natera de Benito D,
Lochmüller H, Thompson R, Polavarapu K, Beeson D, Cossins J, Rodriguez Cruz PM,
Hackman P, Johari M, Savarese M, Udd B, Horvath R, Capella G, Valle L,
Holinski-Feder E, Laner A, Steinke-Lange V, Schröck E, Rump A.

Author information:
(1)Division of Evolution, Infection and Genomics, School of Biological Sciences,
Faculty of Biology, Medicine and Health, University of Manchester, Manchester,
UK.
(2)Manchester Centre for Genomic Medicine, St Mary’s Hospital, Manchester
University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK.
(3)Genes and Human Disease Research Program, Oklahoma Medical Research
Foundation, Oklahoma City, OK, USA.
(4)Department of Dermatology, Birmingham Children’s Hospital, Birmingham Women’s
and Children’s NHS Foundation Trust, Birmingham, UK.
(5)West Midlands Regional Genetics Laboratory, Birmingham Women’s and Children’s
NHS Foundation Trust, Birmingham, UK.
(6)Clinical Genetics, Addenbrooke’s Hospital, Cambridge, UK.
(7)Department of Pediatric Dentistry, Guy’s and St Thomas’ Dental Institute,
London, UK.
(8)Department of Dermatology, Cambridge University Hospitals NHS Foundation
Trust, Cambridge, UK.
(9)North East Thames Regional Genetics Service, Great Ormond Street Hospital for
Children, Great Ormond Street NHS Foundation Trust, London, UK.
(10)Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS
Foundation Trust, Oxford, UK.
(11)Department of Clinical Genetics, St Michael’s Hospital, Bristol, UK.
(12)Department of Genetic Medicine, Belfast HSC Trust, Lisburn Road, Belfast,
UK.
(13)Department of Earth and Environmental Sciences, Manchester Institute of
Biotechnology, University of Manchester, Manchester, UK.
(14)Division of Cell Matrix Biology and Regenerative Medicine, Faculty of
Biology, Medicine and Health, University of Manchester, 99 Oxford Road,
Manchester, UK.

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.

© 2023 The Author(s).

DOI: 10.1016/j.xhgg.2023.100186
PMCID: PMC10064225
PMID: 37009414 [Indexed for MEDLINE]

Conflict of interest statement: The authors declare no competing interests.

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