Bi-allelic WDHD1 variants cause microcephalic primordial dwarfism.
СтатьяНазвание и аннотация: Перевод в очереди
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Tibbe Debora, Vogt Marie Ronja, Holling Tess, Schlieben Lea Dewi, Kortüm Fanny, Shoukier Moneef, Bagowski Christoph, Distelmaier Felix, Averdunk Luisa, Knaus Alexej, Krawitz Peter, Kuechler Alma, Lainka Elke, Stalke Amelie, von Hardenberg Sandra, Auber Bernd, Pfister Eva-Doreen, Reversade Bruno, Sabbagh Anthony, Bertoli-Avella Aida M, Alawbathani Salem, Palmer Elizabeth E, Chauhan Manisha, Rius Rocio, Kim Yoonji, Australian Undiagnosed Diseases Network (UDN-Aus), Papingi Dzhoy, Bartholdi Deborah, Braun Dominique, Maier Oliver, Dinwiddie April, Steichen-Gersdorf Elisabeth, Janecke Andreas R, Tiulpakov Anatoly, Zernov Nikolay, Arismendi Maria Izabel, Jorge Alexander A L, Goel Himanshu, Dreyer Lauren, Loughman Lily, Prokisch Holger, Borgmann Kerstin, Kutsche Kerstin
Аннотация
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.