PuSH - Publication Server of Helmholtz Zentrum München

Tibbe, D.* ; Vogt, M.R.* ; Holling, T.* ; Schlieben, L.D.* ; Kortüm, F.* ; Shoukier, M.* ; Bagowski, C.* ; Distelmaier, F.* ; Averdunk, L.* ; Knaus, A.* ; Krawitz, P.* ; Kuechler, A.* ; Lainka, E.* ; Stalke, A.* ; von Hardenberg, S.* ; Auber, B.* ; Pfister, E.D.* ; Reversade, B.* ; Sabbagh, A.* ; Bertoli-Avella, A.M.* ; Alawbathani, S.* ; Palmer, E.E.* ; Chauhan, M.* ; Rius, R.* ; Kim, Y.* ; Papingi, D.* ; Bartholdi, D.* ; Braun, D.* ; Maier, O.* ; Dinwiddie, A.* ; Steichen-Gersdorf, E.* ; Janecke, A.R.* ; Tiulpakov, A.* ; Zernov, N.* ; Arismendi, M.I.* ; Jorge, A.A.L.* ; Goel, H.* ; Dreyer, L.* ; Loughman, L.* ; Prokisch, H. ; Borgmann, K.* ; Kutsche, K.*

Bi-allelic WDHD1 variants cause microcephalic primordial dwarfism.

Am. J. Hum. Genet. 113, 1067-1089 (2026)
Publ. Version/Full Text Research data DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
DNA replication is carried out by the replisome and is essential for maintaining genome integrity and cell proliferation. Pathogenic variants in genes encoding various replisome components cause microcephalic primordial dwarfism (MPD), characterized by growth retardation, microcephaly, and developmental abnormalities. Here, we report bi-allelic hypomorphic variants in WDHD1 as a cause of MPD with a broad spectrum of additional abnormalities, including acute liver failure, in 17 subjects from 14 families. WDHD1 encodes a replisome scaffolding protein (also known as AND-1 and Ctf4), which is essential for replisome assembly, replication fork stability, and sister chromatid cohesion. We found aberrant splicing of WDHD1 pre-mRNAs for all intronic variants tested and markedly reduced WDHD1 protein levels in subject-derived fibroblasts. Fibroblasts with bi-allelic WDHD1 variants showed globally reduced replication fork speed and impaired replication control, accompanied by spontaneous DNA damage and a G1-to-S transition defect. Using various cell biology approaches, we show that subject fibroblasts displayed reduced proliferation, abnormal nuclear morphology, including micronuclei, multilobed, and enlarged nuclei, as well as an increased number of metaphases with premature sister chromatid separation. Together, our findings establish WDHD1 as a protein required for normal organismal growth and development in humans and underscore its multiple functions in maintaining genome integrity.
Altmetric
Additional Metrics?
[➜Log in]
Edit extra informations Login
Publication type Article: Journal article
Document type Scientific Article
Keywords Dna Replication ; Dna Replication Stress ; Meier-gorlin Syndrome ; Wdhd1 ; Checkpoint ; Genomic Integrity ; Hypomorphic Variants ; Microcephaly ; Replication Fork ; Sister Chromatid Cohesion
ISSN (print) / ISBN 0002-9297
e-ISSN 1537-6605
Journal American Journal of Human Genetics, The
Quellenangaben Volume: 113, Issue: 5, Pages: 1067-1089 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place New York, NY
Reviewing status Peer reviewed
Institute(s) Institute of Neurogenomics (ING)