Open AccessHeterozygous loss of WBP11 function causes multiple congenital defects in humans and mice
Author(s) -
Ella M.M.A. Martin,
Annabelle Enriquez,
Duncan B. Sparrow,
David T. Humphreys,
Aideen McInerneyLeo,
Paul Leo,
Emma L. Duncan,
Kavitha R. Iyer,
Joelene A Greasby,
Eddie Ip,
Eleni Giannoulatou,
Delicia Z. Sheng,
Elizabeth Wohler,
Clémantine Dimartino,
Jeanne Amiel,
Yline Capri,
Daphné Lehalle,
Adi Mory,
Yael Wilnai,
Yael Lebenthal,
Ali G. Gharavi,
Grażyna Krzemień,
Monika Miklaszewska,
Robert D. Steiner,
Cathy Raggio,
Robert D. Blank,
Hagit Baris Feldman,
Hila Milo Rasouly,
Nara Sobreira,
Rebekah Jobling,
Christopher T. Gordon,
Philip F. Giampietro,
Sally L. Dunwoodie,
Gavin Chapman
Publication year - 2020
Publication title -
human molecular genetics online/human molecular genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.811
H-Index - 276
eISSN - 1460-2083
pISSN - 0964-6906
DOI - 10.1093/hmg/ddaa258
Subject(s) - biology , null allele , haploinsufficiency , loss function , heterozygote advantage , genetics , missense mutation , allele , mutation , gene , phenotype
The genetic causes of multiple congenital anomalies are incompletely understood. Here, we report novel heterozygous predicted loss-of-function (LoF) and predicted damaging missense variants in the WW domain binding protein 11 (WBP11) gene in seven unrelated families with a variety of overlapping congenital malformations, including cardiac, vertebral, tracheo-esophageal, renal and limb defects. WBP11 encodes a component of the spliceosome with the ability to activate pre-messenger RNA splicing. We generated a Wbp11 null allele in mouse using CRISPR-Cas9 targeting. Wbp11 homozygous null embryos die prior to E8.5, indicating that Wbp11 is essential for development. Fewer Wbp11 heterozygous null mice are found than expected due to embryonic and postnatal death. Importantly, Wbp11 heterozygous null mice are small and exhibit defects in axial skeleton, kidneys and esophagus, similar to the affected individuals, supporting the role of WBP11 haploinsufficiency in the development of congenital malformations in humans. LoF WBP11 variants should be considered as a possible cause of VACTERL association as well as isolated Klippel-Feil syndrome, renal agenesis or esophageal atresia.