Loss-of-Function GRHL3 Variants Detected in African Patients with Isolated Cleft Palate

M A Eshete; H Liu; M Li; W L Adeyemo; L J J Gowans; P A Mossey; T Busch; W Deressa; P Donkor; P B Olaitan; B S Aregbesola; R O Braimah; G O Oseni; F Oginni; R Audu; C Onwuamah; O James; E Augustine-Akpan; L A Rahman; M O Ogunlewe; F K N Arthur; S A Bello; P Agbenorku; P Twumasi; F Abate; T Hailu; Y Demissie; A Hailu; G Plange-Rhule; S Obiri-Yeboah; M M Dunnwald; P E Gravem; M L Marazita; A A Adeyemo; J C Murray; R A Cornell; A Butali

doi:10.1177/0022034517729819

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Loss-of-Function GRHL3 Variants Detected in African Patients with Isolated Cleft Palate

Journal article

Open access

Peer reviewed

Loss-of-Function GRHL3 Variants Detected in African Patients with Isolated Cleft Palate

M A Eshete, H Liu, M Li, W L Adeyemo, L J J Gowans, P A Mossey, T Busch, W Deressa, P Donkor, P B Olaitan, …

Journal of dental research, Vol.97(1), pp.41-48

01/2018

DOI: 10.1177/0022034517729819

PMCID: PMC5755809

PMID: 28886269

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Abstract

In contrast to the progress that has been made toward understanding the genetic etiology of cleft lip with or without cleft palate, relatively little is known about the genetic etiology for cleft palate only (CPO). A common coding variant of grainyhead like transcription factor 3 ( GRHL3) was recently shown to be associated with risk for CPO in Europeans. Mutations in this gene were also reported in families with Van der Woude syndrome. To identify rare mutations in GRHL3 that might explain the missing heritability for CPO, we sequenced GRHL3 in cases of CPO from Africa. We recruited participants from Ghana, Ethiopia, and Nigeria. This cohort included case-parent trios, cases and other family members, as well as controls. We sequenced exons of this gene in DNA from a total of 134 nonsyndromic cases. When possible, we sequenced them in parents to identify de novo mutations. Five novel mutations were identified: 2 missense (c.497C>A; p.Pro166His and c.1229A>G; p.Asp410Gly), 1 splice site (c.1282A>C p.Ser428Arg), 1 frameshift (c.470delC; p.Gly158Alafster55), and 1 nonsense (c.1677C>A; p.Tyr559Ter). These mutations were absent from 270 sequenced controls and from all public exome and whole genome databases, including the 1000 Genomes database (which includes data from Africa). However, 4 of the 5 mutations were present in unaffected mothers, indicating that their penetrance is incomplete. Interestingly, 1 mutation damaged a predicted sumoylation site, and another disrupted a predicted CK1 phosphorylation site. Overexpression assays in zebrafish and reporter assays in vitro indicated that 4 variants were functionally null or hypomorphic, while 1 was dominant negative. This study provides evidence that, as in Caucasian populations, mutations in GRHL3 contribute to the risk of nonsyndromic CPO in the African population.

Genome-Wide Association Study

Mutagenesis, Site-Directed

RNA Splice Sites - genetics

Humans

Cleft Palate - genetics

Transcription Factors - genetics

DNA-Binding Proteins - genetics

Zebrafish - embryology

Mutation, Missense - genetics

Zebrafish - genetics

Animals

African Continental Ancestry Group - genetics

Codon, Nonsense - genetics

Frameshift Mutation - genetics

Loss of Function Mutation - genetics

Details

Title: Subtitle: Loss-of-Function GRHL3 Variants Detected in African Patients with Isolated Cleft Palate
Creators: M A Eshete - 3 Department of Surgery, School of Medicine, Addis Ababa University, Addis Ababa, Ethiopia
H Liu - 5 State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory for Oral Biomedicine of Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China
M Li - 6 Department of Oral Pathology, Radiology and Medicine, University of Iowa, Iowa City, IA, USA
W L Adeyemo - 7 Department of Oral and Maxillofacial Surgery, University of Lagos, Lagos, Nigeria
L J J Gowans - 8 Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
P A Mossey - 9 Department of Orthodontics, University of Dundee, Dundee, UK
T Busch - 6 Department of Oral Pathology, Radiology and Medicine, University of Iowa, Iowa City, IA, USA
W Deressa - 1 School of Public Health, Addis Ababa University, Addis Ababa, Ethiopia
P Donkor - 8 Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
P B Olaitan - 10 Department of Plastic Surgery, Ladoke Akintola University of Science and Technology, Osogbo, Nigeria
B S Aregbesola - 11 Department of Oral and Maxillofacial Surgery, Obafemi Awolowo University, Ile Ife, Nigeria
R O Braimah - 12 Department of Oral and Maxillofacial Surgery, Usmanu Danfodiyo University, Sokoto, Nigeria
G O Oseni - 10 Department of Plastic Surgery, Ladoke Akintola University of Science and Technology, Osogbo, Nigeria
F Oginni - 11 Department of Oral and Maxillofacial Surgery, Obafemi Awolowo University, Ile Ife, Nigeria
R Audu - 13 Department of Virology, Nigerian Institute of Medical Research, Lagos, Nigeria
C Onwuamah - 13 Department of Virology, Nigerian Institute of Medical Research, Lagos, Nigeria
O James - 7 Department of Oral and Maxillofacial Surgery, University of Lagos, Lagos, Nigeria
E Augustine-Akpan - 6 Department of Oral Pathology, Radiology and Medicine, University of Iowa, Iowa City, IA, USA
L A Rahman - 14 Division of Pediatric Surgery, Department of Surgery, University of Ilorin, Ilorin, Nigeria
M O Ogunlewe - 7 Department of Oral and Maxillofacial Surgery, University of Lagos, Lagos, Nigeria
F K N Arthur - 8 Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
S A Bello - 15 State House Clinic, Abuja, Nigeria
P Agbenorku - 8 Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
P Twumasi - 8 Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
F Abate - 2 Yekatit 12 Hospital Medical College, Addis Ababa, Ethiopia
T Hailu - 2 Yekatit 12 Hospital Medical College, Addis Ababa, Ethiopia
Y Demissie - 3 Department of Surgery, School of Medicine, Addis Ababa University, Addis Ababa, Ethiopia
A Hailu - 3 Department of Surgery, School of Medicine, Addis Ababa University, Addis Ababa, Ethiopia
G Plange-Rhule - 8 Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
S Obiri-Yeboah - 8 Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
M M Dunnwald - 4 Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IA, USA
P E Gravem - 16 Plastic and Reconstructive Surgery Department, Haukeland University Hospital, Bergen, Norway
M L Marazita - 17 Center for Craniofacial and Dental Genetics, Department of Oral Biology, University of Pittsburgh, Pittsburgh, PA, USA
A A Adeyemo - 18 National Human Genomic Research Institute, Bethesda, MD, USA
J C Murray - 19 Department of Pediatrics University of Iowa, Iowa City, IA, USA
R A Cornell - 4 Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IA, USA
A Butali - 6 Department of Oral Pathology, Radiology and Medicine, University of Iowa, Iowa City, IA, USA
Resource Type: Journal article
Publication Details: Journal of dental research, Vol.97(1), pp.41-48
DOI: 10.1177/0022034517729819
PMID: 28886269
PMCID: PMC5755809
NLM abbreviation: J Dent Res
ISSN: 0022-0345
eISSN: 1544-0591
Publisher: United States
Grant note: R01 DE023575 / NIDCR NIH HHS K99 DE022378 / NIDCR NIH HHS R01 AR067739 / NIAMS NIH HHS R00 DE022378 / NIDCR NIH HHS R01 DE016148 / NIDCR NIH HHS R01 DE008559 / NIDCR NIH HHS R37 DE008559 / NIDCR NIH HHS
Language: English
Date published: 01/2018
Academic Unit: Oral Pathology, Radiology and Medicine; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Epidemiology; Pediatric Dentistry; Craniofacial Anomalies Research Center; Dental Research
Record Identifier: 9984025355202771

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