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Am J Hum Genet. 2019 Mar 7;104(3):422-438. doi: 10.1016/j.ajhg.2019.01.007. Epub 2019 Feb 14.

Bi-allelic Variants in TONSL Cause SPONASTRIME Dysplasia and a Spectrum of Skeletal Dysplasia Phenotypes.

Collaborators (201)

Adams DR, Aday A, Alejandro ME, Allard P, Ashley EA, Azamian MS, Bacino CA, Baker E, Balasubramanyam A, Barseghyan H, Batzli GF, Beggs AH, Behnam B, Bellen HJ, Bernstein JA, Berry GT, Bican A, Bick DP, Birch CL, Bonner D, Boone BE, Bostwick BL, Briere LC, Brokamp E, Brown DM, Brush M, Burke EA, Burrage LC, Butte MJ, Chen S, Clark GD, Coakley TR, Cogan JD, Colley HA, Cooper CM, Cope H, Craigen WJ, D'Souza P, Davids M, Davidson JM, Dayal JG, Dell'Angelica EC, Dhar SU, Dipple KM, Donnell-Fink LA, Dorrani N, Dorset DC, Douine ED, Draper DD, Dries AM, Duncan L, Eckstein DJ, Emrick LT, Eng CM, Enns GM, Eskin A, Esteves C, Estwick T, Fernandez L, Ferreira C, Fieg EL, Fisher PG, Fogel BL, Friedman ND, Gahl WA, Glanton E, Godfrey RA, Goldman AM, Goldstein DB, Gould SE, Gourdine JF, Groden CA, Gropman AL, Haendel M, Hamid R, Hanchard NA, High F, Holm IA, Hom J, Howerton EM, Huang Y, Jamal F, Jiang YH, Johnston JM, Jones AL, Karaviti L, Koeller DM, Kohane IS, Kohler JN, Krasnewich DM, Korrick S, Koziura M, Krier JB, Kyle JE, Lalani SR, Lau CC, Lazar J, LeBlanc K, Lee BH, Lee H, Levy SE, Lewis RA, Lincoln SA, Loo SK, Loscalzo J, Maas RL, Macnamara EF, MacRae CA, Maduro VV, Majcherska MM, Malicdan MCV, Mamounas LA, Manolio TA, Markello TC, Marom R, Martin MG, Martínez-Agosto JA, Marwaha S, May T, McConkie-Rosell A, McCormack CE, McCray AT, Merker JD, Metz TO, Might M, Moretti PM, Morimoto M, Mulvihill JJ, Murdock DR, Murphy JL, Muzny DM, Nehrebecky ME, Nelson SF, Newberry JS, Newman JH, Nicholas SK, Novacic D, Orange JS, Orengo JP, Pallais JC, Palmer CGS, Papp JC, Parker NH, Pena LDM, Phillips JA 3rd, Posey JE, Postlethwait JH, Potocki L, Pusey BN, Renteria G, Reuter CM, Rives L, Robertson AK, Rodan LH, Rosenfeld JA, Sampson JB, Samson SL, Schoch K, Scott DA, Shakachite L, Sharma P, Shashi V, Signer R, Silverman EK, Sinsheimer JS, Smith KS, Spillmann RC, Stoler JM, Stong N, Sullivan JA, Sweetser DA, Tan QK, Tifft CJ, Toro C, Tran AA, Urv TK, Vilain E, Vogel TP, Waggott DM, Wahl CE, Walley NM, Walsh CA, Walker M, Wan J, Wangler MF, Ward PA, Waters KM, Webb-Robertson BM, Westerfield M, Wheeler MT, Wise AL, Wolfe LA, Worthey EA, Yamamoto S, Yang J, Yang Y, Yoon AJ, Yu G, Zastrow DB, Zhao C, Zheng A.

Author information

1
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
2
Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham B15 2TT, UK.
3
Centre Hospitalier Universitaire Sainte-Justine Research Center, University of Montreal, Montreal, QC H3T1J4, Canada.
4
Institute of Neuroscience, University of Oregon, Eugene, OR 97403, USA.
5
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
6
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
7
Department of Bone and Osteogenesis Imperfecta, Kennedy Krieger Institute, Baltimore, MD 21205, USA.
8
Medical Research Council Institute of Genetics & Molecular Medicine, the University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK.
9
Division of Pediatric Endocrinology and Diabetes, University of Utah, Salt Lake City, UT 84112, USA.
10
The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, ON M5G 1Z5, Canada; Department of Pediatrics, Division of Clinical and Metabolic Genetics, the Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1X8, Canada.
11
Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Division of Pediatric Immunology, Allergy, and Rheumatology, Texas Children's Hospital, Houston, TX 77030, USA.
12
Division of Diabetes and Endocrinology, Texas Children's Hospital, Houston, TX 77030, USA.
13
Department of Pediatric Radiology, Texas Children's Hospital, Houston, TX 77030, USA; Department of Radiology, Baylor College of Medicine, Houston, TX 77030, USA.
14
Seattle Children's Hospital, Seattle, WA 98195, USA.
15
Seattle Children's Hospital, Seattle, WA 98195, USA; Departments of Pediatrics and Genome Sciences, University of Washington, Seattle, WA 98195, USA.
16
Victorian Clinical Genetics Services, Murdoch Children's Research Institute, University of Melbourne, Parkville, VIC 3052, Australia.
17
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
18
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston, TX 77030, USA.
19
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
20
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Division of Neurology and Developmental Neuroscience and Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
21
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
22
Service of Genetic Medicine, University of Geneva Medical School, Geneva University Hospitals, 1205 Geneva, Switzerland.
23
Department of Genetics, INSERM UMR1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, AP-HP, Hôpital Necker Enfants Malades, Paris 75015, France.
24
Associated Regional and University Pathologists Laboratories, Salt Lake City, UT 84108, USA; Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA.
25
Division of Pediatric Immunology, Allergy, and Rheumatology, Texas Children's Hospital, Houston, TX 77030, USA; Current affiliation: Department of Pediatrics, Columbia University Vagelos College of Physicians and Surgeons, New York Presbyterian, New York, NY 10032, USA.
26
Clinical Genetics Unit, Instituto da Criança, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP 05403-000, Brazil; Centro de Pesquisa sobre o Genoma Humano e Células-Tronco, Instituto de Biociências da Universidade de São Paulo, SP 05508-0900, Brazil.
27
Clinical Genetics Unit, Instituto da Criança, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP 05403-000, Brazil.
28
Departments of Psychiatry and Behavioral Sciences and Pediatrics, Kansas University Medical Center, Kansas City, KS 66160, USA.
29
Department of Ophthalmology and Vision Sciences, the Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1X8, Canada.
30
Department of Allergy and Immunology, Sidra Medicine, Hamad Medical Corporation, Weill Cornell Medicine, Qatar, Doha, Qatar.
31
Department of Molecular, Cell, and Developmental Biology and Department of Orthopaedic Surgery, University of California, Los Angeles, Los Angeles, CA 90095, USA.
32
Department of Orthopaedic Surgery, Department of Human Genetics and Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, CA 90095, USA.
33
Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
34
North East Thames Regional Genetics Service, Great Ormond Street Hospital, London WC1N 3JH, UK.
35
Department of Oncology and Metabolism, Academic Unit of Child Health, University of Sheffield, Sheffield S10 2TH, UK.
36
Department of Pediatrics, Division of Medical Genetics, University of Utah, Salt Lake City, UT 84112, USA.
37
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA. Electronic address: blee@bcm.edu.

Abstract

SPONASTRIME dysplasia is an autosomal-recessive spondyloepimetaphyseal dysplasia characterized by spine (spondylar) abnormalities, midface hypoplasia with a depressed nasal bridge, metaphyseal striations, and disproportionate short stature. Scoliosis, coxa vara, childhood cataracts, short dental roots, and hypogammaglobulinemia have also been reported in this disorder. Although an autosomal-recessive inheritance pattern has been hypothesized, pathogenic variants in a specific gene have not been discovered in individuals with SPONASTRIME dysplasia. Here, we identified bi-allelic variants in TONSL, which encodes the Tonsoku-like DNA repair protein, in nine subjects (from eight families) with SPONASTRIME dysplasia, and four subjects (from three families) with short stature of varied severity and spondylometaphyseal dysplasia with or without immunologic and hematologic abnormalities, but no definitive metaphyseal striations at diagnosis. The finding of early embryonic lethality in a Tonsl-/- murine model and the discovery of reduced length, spinal abnormalities, reduced numbers of neutrophils, and early lethality in a tonsl-/- zebrafish model both support the hypomorphic nature of the identified TONSL variants. Moreover, functional studies revealed increased amounts of spontaneous replication fork stalling and chromosomal aberrations, as well as fewer camptothecin (CPT)-induced RAD51 foci in subject-derived cell lines. Importantly, these cellular defects were rescued upon re-expression of wild-type (WT) TONSL; this rescue is consistent with the hypothesis that hypomorphic TONSL variants are pathogenic. Overall, our studies in humans, mice, zebrafish, and subject-derived cell lines confirm that pathogenic variants in TONSL impair DNA replication and homologous recombination-dependent repair processes, and they lead to a spectrum of skeletal dysplasia phenotypes with numerous extra-skeletal manifestations.

KEYWORDS:

DNA repair; DNA replication; SPONASTRIME dysplasia; TONSL; exome sequencing; skeletal dysplasia

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