Heterozygous loss of WBP11 function causes multiple congenital defects in humans and mice

Ella M.M.A. Martin; Annabelle Enriquez; Duncan B. Sparrow; David T. Humphreys; Aideen M. McInerney-Leo; Paul J. Leo; Emma L. Duncan; Kavitha R. Iyer; Joelene A. Greasby; Eddie Ip; Eleni Giannoulatou; Delicia Sheng; Elizabeth Wohler; Clémantine Dimartino; Jeanne Amiel; Yline Capri; Daphné Lehalle; Adi Mory; Yael Wilnai; Yael Lebenthal; Ali G. Gharavi; Grazyna G. Krzemień; Monika Miklaszewska; Robert D. Steiner; Cathy Raggio; Robert Blank; Hagit Baris Feldman; Hila Milo Rasouly; Nara L.M. Sobreira; Rebekah Jobling; Christopher T. Gordon; Philip F. Giampietro; Sally L. Dunwoodie; Gavin Chapman

doi:10.1093/hmg/ddaa258

Heterozygous loss of WBP11 function causes multiple congenital defects in humans and mice

Ella M.M.A. Martin, Annabelle Enriquez, Duncan B. Sparrow, David T. Humphreys, Aideen M. McInerney-Leo, Paul J. Leo, Emma L. Duncan, Kavitha R. Iyer, Joelene A. Greasby, Eddie Ip, Eleni Giannoulatou, Delicia Sheng, Elizabeth Wohler, Clémantine Dimartino, Jeanne Amiel, Yline Capri, Daphné Lehalle, Adi Mory, Yael Wilnai, Yael LebenthalAli G. Gharavi, Grazyna G. Krzemień, Monika Miklaszewska, Robert D. Steiner, Cathy Raggio, Robert Blank, Hagit Baris Feldman, Hila Milo Rasouly, Nara L.M. Sobreira, Rebekah Jobling, Christopher T. Gordon, Philip F. Giampietro, Sally L. Dunwoodie, Gavin Chapman^*

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Pages (from-to)	3662-3678
Number of pages	17
Journal	Human Molecular Genetics
Volume	29
Issue number	22
DOIs	https://doi.org/10.1093/hmg/ddaa258
State	Published - 15 Nov 2020

Access to Document

10.1093/hmg/ddaa258

Cite this

Martin, E. M. M. A., Enriquez, A., Sparrow, D. B., Humphreys, D. T., McInerney-Leo, A. M., Leo, P. J., Duncan, E. L., Iyer, K. R., Greasby, J. A., Ip, E., Giannoulatou, E., Sheng, D., Wohler, E., Dimartino, C., Amiel, J., Capri, Y., Lehalle, D., Mory, A., Wilnai, Y., ... Chapman, G. (2020). Heterozygous loss of WBP11 function causes multiple congenital defects in humans and mice. Human Molecular Genetics, 29(22), 3662-3678. https://doi.org/10.1093/hmg/ddaa258

@article{2cbedea2df29426a88111d8098f41617,

title = "Heterozygous loss of WBP11 function causes multiple congenital defects in humans and mice",

abstract = "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.",

author = "Martin, {Ella M.M.A.} and Annabelle Enriquez and Sparrow, {Duncan B.} and Humphreys, {David T.} and McInerney-Leo, {Aideen M.} and Leo, {Paul J.} and Duncan, {Emma L.} and Iyer, {Kavitha R.} and Greasby, {Joelene A.} and Eddie Ip and Eleni Giannoulatou and Delicia Sheng and Elizabeth Wohler and Cl{\'e}mantine Dimartino and Jeanne Amiel and Yline Capri and Daphn{\'e} Lehalle and Adi Mory and Yael Wilnai and Yael Lebenthal and Gharavi, {Ali G.} and Krzemie{\'n}, {Grazyna G.} and Monika Miklaszewska and Steiner, {Robert D.} and Cathy Raggio and Robert Blank and {Baris Feldman}, Hagit and {Milo Rasouly}, Hila and Sobreira, {Nara L.M.} and Rebekah Jobling and Gordon, {Christopher T.} and Giampietro, {Philip F.} and Dunwoodie, {Sally L.} and Gavin Chapman",

year = "2020",

month = nov,

day = "15",

doi = "10.1093/hmg/ddaa258",

language = "אנגלית",

volume = "29",

pages = "3662--3678",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "22",

}

Martin, EMMA, Enriquez, A, Sparrow, DB, Humphreys, DT, McInerney-Leo, AM, Leo, PJ, Duncan, EL, Iyer, KR, Greasby, JA, Ip, E, Giannoulatou, E, Sheng, D, Wohler, E, Dimartino, C, Amiel, J, Capri, Y, Lehalle, D, Mory, A, Wilnai, Y, Lebenthal, Y, Gharavi, AG, Krzemień, GG, Miklaszewska, M, Steiner, RD, Raggio, C, Blank, R, Baris Feldman, H, Milo Rasouly, H, Sobreira, NLM, Jobling, R, Gordon, CT, Giampietro, PF, Dunwoodie, SL & Chapman, G 2020, 'Heterozygous loss of WBP11 function causes multiple congenital defects in humans and mice', Human Molecular Genetics, vol. 29, no. 22, pp. 3662-3678. https://doi.org/10.1093/hmg/ddaa258

TY - JOUR

T1 - Heterozygous loss of WBP11 function causes multiple congenital defects in humans and mice

AU - Martin, Ella M.M.A.

AU - Enriquez, Annabelle

AU - Sparrow, Duncan B.

AU - Humphreys, David T.

AU - McInerney-Leo, Aideen M.

AU - Leo, Paul J.

AU - Duncan, Emma L.

AU - Iyer, Kavitha R.

AU - Greasby, Joelene A.

AU - Ip, Eddie

AU - Giannoulatou, Eleni

AU - Sheng, Delicia

AU - Wohler, Elizabeth

AU - Dimartino, Clémantine

AU - Amiel, Jeanne

AU - Capri, Yline

AU - Lehalle, Daphné

AU - Mory, Adi

AU - Wilnai, Yael

AU - Lebenthal, Yael

AU - Gharavi, Ali G.

AU - Krzemień, Grazyna G.

AU - Miklaszewska, Monika

AU - Steiner, Robert D.

AU - Raggio, Cathy

AU - Blank, Robert

AU - Baris Feldman, Hagit

AU - Milo Rasouly, Hila

AU - Sobreira, Nara L.M.

AU - Jobling, Rebekah

AU - Gordon, Christopher T.

AU - Giampietro, Philip F.

AU - Dunwoodie, Sally L.

AU - Chapman, Gavin

PY - 2020/11/15

Y1 - 2020/11/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85100358628&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddaa258

DO - 10.1093/hmg/ddaa258

M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???

C2 - 33276377

AN - SCOPUS:85100358628

SN - 0964-6906

VL - 29

SP - 3662

EP - 3678

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 22

ER -

Heterozygous loss of WBP11 function causes multiple congenital defects in humans and mice

Abstract

Access to Document

Other files and links

Fingerprint

Cite this