Article Dans Une Revue Nature Communications Année : 2022

Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy

Laura J Grange
John J Reynolds
Ryan M Baxley
Antony W Oliver
Sophie L Cooke
Satpal S Jhujh
Martin R Higgs
Tahir Khan
Gabriel Á Martos-Moreno
  • Fonction : Auteur
Sharon Chupp
  • Fonction : Auteur
Michael A Simpson
Zafer Yüksel
Anja Kron
  • Fonction : Auteur
Petra Vogt
  • Fonction : Auteur
Saad Ahmed Seth
Karlla W Brigatti
  • Fonction : Auteur
Yuri Uchiyama
Hitoshi Osaka
Zineb Ammous
  • Fonction : Auteur
Naomichi Matsumoto
Anja-Katrin Bielinsky
Niels Mailand
Erica E Davis
Grant S Stewart

Résumé

Embryonic development is dictated by tight regulation of DNA replication, cell division and differentiation. Mutations in DNA repair and replication genes disrupt this equilibrium, giving rise to neurodevelopmental disease characterized by microcephaly, short stature and chromosomal breakage. Here, we identify biallelic variants in two components of the RAD18-SLF1/2-SMC5/6 genome stability pathway, SLF2 and SMC5, in 11 patients with microcephaly, short stature, cardiac abnormalities and anemia. Patient-derived cells exhibit a unique chromosomal instability phenotype consisting of segmented and dicentric chromosomes with mosaic variegated hyperploidy. To signify the importance of these segmented chromosomes, we have named this disorder Atelís (meaning - incomplete) Syndrome. Analysis of Atelís Syndrome cells reveals elevated levels of replication stress, partly due to a reduced ability to replicate through G-quadruplex DNA structures, and also loss of sister chromatid cohesion. Together, these data strengthen the functional link between SLF2 and the SMC5/6 complex, highlighting a distinct role for this pathway in maintaining genome stability.
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hal-04708402 , version 1 (24-09-2024)

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Laura J Grange, John J Reynolds, Farid Ullah, Bertrand Isidor, Robert F Shearer, et al.. Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy. Nature Communications, 2022, 13 (1), pp.6664. ⟨10.1038/s41467-022-34349-8⟩. ⟨hal-04708402⟩
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