Mosaic-variegated aneuploidy syndrome mutation or haploinsufficiency in Cep57 impairs tumor suppression

Khaled Aziz, Cynthia J. Sieben, Karthik B. Jeganathan, Masakazu Hamada, Brian A. Davies, Raul O. Fierro Velasco, Nazneen Rahman, David J Katzmann, Jan Van Deursen

Research output: Contribution to journalArticle

Abstract

A homozygous truncating frameshift mutation in CEP57 (CEP57T/T) has been identified in a subset of mosaic-variegated aneuploidy (MVA) patients; however, the physiological roles of the centrosome-associated protein CEP57 that contribute to disease are unknown. To investigate these, we have generated a mouse model mimicking this disease mutation. Cep57T/T mice died within 24 hours after birth with short, curly tails and severely impaired vertebral ossification. Osteoblasts in lumbosacral vertebrae of Cep57T/T mice were deficient for Fgf2, a Cep57 binding partner implicated in diverse biological processes, including bone formation. Furthermore, a broad spectrum of tissues of Cep57T/T mice had severe aneuploidy at birth, consistent with the MVA patient phenotype. Cep57T/T mouse embryonic fibroblasts and patient-derived skin fibroblasts failed to undergo centrosome maturation in G2 phase, causing premature centriole disjunction, centrosome amplification, aberrant spindle formation, and high rates of chromosome missegregation. Mice heterozygous for the truncating frameshift mutation or a Cep57-null allele were overtly indistinguishable from WT mice despite reduced Cep57 protein levels, yet prone to aneuploidization and cancer, with tumors lacking evidence for loss of heterozygosity. This study identifies Cep57 as a haploinsufficient tumor suppressor with biologically diverse roles in centrosome maturation and Fgf2-mediated bone formation.

Original languageEnglish (US)
Pages (from-to)3517-3534
Number of pages18
JournalJournal of Clinical Investigation
Volume128
Issue number8
DOIs
StatePublished - Aug 1 2018

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Haploinsufficiency
Centrosome
Mutation
Aneuploidy
Neoplasms
Osteogenesis
Frameshift Mutation
Fibroblasts
Parturition
Centrioles
Biological Phenomena
Loss of Heterozygosity
G2 Phase
Mosaic variegated aneuploidy syndrome
Osteoblasts
Tail
Proteins
Spine
Chromosomes
Alleles

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Mosaic-variegated aneuploidy syndrome mutation or haploinsufficiency in Cep57 impairs tumor suppression. / Aziz, Khaled; Sieben, Cynthia J.; Jeganathan, Karthik B.; Hamada, Masakazu; Davies, Brian A.; Fierro Velasco, Raul O.; Rahman, Nazneen; Katzmann, David J; Van Deursen, Jan.

In: Journal of Clinical Investigation, Vol. 128, No. 8, 01.08.2018, p. 3517-3534.

Research output: Contribution to journalArticle

Aziz, K, Sieben, CJ, Jeganathan, KB, Hamada, M, Davies, BA, Fierro Velasco, RO, Rahman, N, Katzmann, DJ & Van Deursen, J 2018, 'Mosaic-variegated aneuploidy syndrome mutation or haploinsufficiency in Cep57 impairs tumor suppression', Journal of Clinical Investigation, vol. 128, no. 8, pp. 3517-3534. https://doi.org/10.1172/JCI120316
Aziz K, Sieben CJ, Jeganathan KB, Hamada M, Davies BA, Fierro Velasco RO et al. Mosaic-variegated aneuploidy syndrome mutation or haploinsufficiency in Cep57 impairs tumor suppression. Journal of Clinical Investigation. 2018 Aug 1;128(8):3517-3534. https://doi.org/10.1172/JCI120316
Aziz, Khaled ; Sieben, Cynthia J. ; Jeganathan, Karthik B. ; Hamada, Masakazu ; Davies, Brian A. ; Fierro Velasco, Raul O. ; Rahman, Nazneen ; Katzmann, David J ; Van Deursen, Jan. / Mosaic-variegated aneuploidy syndrome mutation or haploinsufficiency in Cep57 impairs tumor suppression. In: Journal of Clinical Investigation. 2018 ; Vol. 128, No. 8. pp. 3517-3534.
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