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

University of Washington Center for Mendelian Genomics, Undiagnosed Diseases Network

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)422-438
Number of pages17
JournalAmerican Journal of Human Genetics
Volume104
Issue number3
DOIs
StatePublished - Mar 7 2019

Fingerprint

Zebrafish
Coxa Vara
Phenotype
Tooth Root
Recombinational DNA Repair
Cell Line
Agammaglobulinemia
Camptothecin
Inheritance Patterns
Scoliosis
DNA Replication
Nose
Chromosome Aberrations
DNA Repair
Cataract
Spine
Neutrophils
Genes
Proteins
Strudwick syndrome

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Bi-allelic Variants in TONSL Cause SPONASTRIME Dysplasia and a Spectrum of Skeletal Dysplasia Phenotypes. / University of Washington Center for Mendelian Genomics; Undiagnosed Diseases Network.

In: American Journal of Human Genetics, Vol. 104, No. 3, 07.03.2019, p. 422-438.

Research output: Contribution to journalArticle

University of Washington Center for Mendelian Genomics & Undiagnosed Diseases Network 2019, 'Bi-allelic Variants in TONSL Cause SPONASTRIME Dysplasia and a Spectrum of Skeletal Dysplasia Phenotypes', American Journal of Human Genetics, vol. 104, no. 3, pp. 422-438. https://doi.org/10.1016/j.ajhg.2019.01.007
University of Washington Center for Mendelian Genomics ; Undiagnosed Diseases Network. / Bi-allelic Variants in TONSL Cause SPONASTRIME Dysplasia and a Spectrum of Skeletal Dysplasia Phenotypes. In: American Journal of Human Genetics. 2019 ; Vol. 104, No. 3. pp. 422-438.
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AU - University of Washington Center for Mendelian Genomics

AU - Undiagnosed Diseases Network

AU - Burrage, Lindsay C.

AU - Lanza, Denise G.

AU - Seavitt, John R.

AU - Li, Xiaohui

AU - Bertuch, Alison A.

AU - Eng, Christine M.

AU - Gibbs, Richard A.

AU - Bi, Weimin

AU - Emrick, Lisa

AU - Rosenfeld, Jill A.

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AU - Bacino, Carlos A.

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AU - Jain, Mahim

AU - Parry, David A.

AU - Raman, Vandana

AU - Chitayat, David

AU - Chitayat, David

AU - Chinn, Ivan K.

AU - Emrick, Lisa

AU - Chinn, Ivan K.

AU - Orange, Jordan S.

AU - Karaviti, Lefkothea

AU - Schlesinger, Alan E.

AU - Schlesinger, Alan E.

AU - Earl, Dawn

AU - Bamshad, Michael

AU - Bamshad, Michael

AU - Savarirayan, Ravi

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KW - SPONASTRIME dysplasia

KW - TONSL

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