A plethora of factors act together in the cell to ensure that DNA is correctly duplicated and distributed to daughter cells during cell division. Scientists have now uncovered a new factor playing a central role in these processes, and they showed that changes in this factor result in disturbed DNA replication and cause microcephalic primordial dwarfism in humans.

A large international study that was led by the groups of Grant Stewart (University of Birmingham) and Andrew Jackson (University of Edinburgh) and to which also Yun Li and Gökhan Yigit, researchers at the Institute of Human Genetics Göttingen, contributed, investigated 29 patients with microcephaly and short stature. Applying latest next-generation sequencing techniques, the scientists detected in the patients changes in the DONSON gene as the cause of their congenital malformation syndrome.

Functional analyses performed in the study demonstrated that DONSON is part of the cell’s replication machinery and is involved in stabilizing the replication fork. The mutations in DONSON found in the patients affect these functions; they decreased the level of functional protein and considerably impaired DNA replication and genomic stability.

These new findings have now been published in Nature Genetics.

Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism
Reynolds JJ, Bicknell LS, Carroll P, Higgs MR, Shaheen R, Murray JE, Papadopoulos DK, Leitch A, Murina O, Tarnauskaitė Ž, Wessel SR, Zlatanou A, Vernet A, von Kriegsheim A, Mottram RM, Logan CV, Bye H, Li Y, Brean A, Maddirevula S, Challis RC, Skouloudaki K, Almoisheer A, Alsaif HS, Amar A, Prescott NJ, Bober MB, Duker A, Faqeih E, Seidahmed MZ, Al Tala S, Alswaid A, Ahmed S, Al-Aama JY, Altmüller J, Al Balwi M, Brady AF, Chessa L, Cox H, Fischetto R, Heller R, Henderson BD, Hobson E, Nürnberg P, Percin EF, Peron A, Spaccini L, Quigley AJ, Thakur S, Wise CA, Yoon G, Alnemer M, Tomancak P, Yigit G, Taylor AM, Reijns MA, Simpson MA, Cortez D, Alkuraya FS, Mathew CG, Jackson AP, Stewart GS.
Nat Genet. 2017 Feb 13. doi: 10.1038/ng.3790. [Epub ahead of print]