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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Alleles
  • Animals
  • Cells, Cultured
  • Child
  • Child, Preschool
  • Chromosomal Instability*
  • DNA Damage*
  • Female
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Genetic Association Studies
  • Genetic Variation*
  • Humans
  • Mice
  • Mice, Knockout
  • Musculoskeletal Abnormalities / genetics
  • Musculoskeletal Abnormalities / pathology*
  • NF-kappa B / genetics*
  • Osteochondrodysplasias / genetics
  • Osteochondrodysplasias / pathology*
  • Whole Exome Sequencing
  • Young Adult
  • Zebrafish

Substances

  • NF-kappa B
  • TONSL protein, human

Supplementary concepts

  • Spondyloepimetaphyseal dysplasia, sponastrime type