A LINE-1 insertion in DLX6 is responsible for cleft palate and mandibular abnormalities in a canine model of Pierre Robin sequence

Zena T Wolf; Elizabeth J Leslie; Boaz Arzi; Kartika Jayashankar; Nili Karmi; Zhonglin Jia; Douglas J Rowland; Amy Young; Noa Safra; Saundra Sliskovic; Jeffrey C Murray; Claire M Wade; Danika L Bannasch

doi:10.1371/journal.pgen.1004257

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A LINE-1 insertion in DLX6 is responsible for cleft palate and mandibular abnormalities in a canine model of Pierre Robin sequence

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A LINE-1 insertion in DLX6 is responsible for cleft palate and mandibular abnormalities in a canine model of Pierre Robin sequence

Zena T Wolf, Elizabeth J Leslie, Boaz Arzi, Kartika Jayashankar, Nili Karmi, Zhonglin Jia, Douglas J Rowland, Amy Young, Noa Safra, Saundra Sliskovic, …

PLoS genetics, Vol.10(4), pp.e1004257-e1004257

04/2014

DOI: 10.1371/journal.pgen.1004257

PMCID: PMC3974639

PMID: 24699068

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Abstract

Cleft palate (CP) is one of the most commonly occurring craniofacial birth defects in humans. In order to study cleft palate in a naturally occurring model system, we utilized the Nova Scotia Duck Tolling Retriever (NSDTR) dog breed. Micro-computed tomography analysis of CP NSDTR craniofacial structures revealed that these dogs exhibit defects similar to those observed in a recognizable subgroup of humans with CP: Pierre Robin Sequence (PRS). We refer to this phenotype in NSDTRs as CP1. Individuals with PRS have a triad of birth defects: shortened mandible, posteriorly placed tongue, and cleft palate. A genome-wide association study in 14 CP NSDTRs and 72 unaffected NSDTRs identified a significantly associated region on canine chromosome 14 (24.2 Mb-29.3 Mb; p(raw )= 4.64 × 10(-15)). Sequencing of two regional candidate homeobox genes in NSDTRs, distal-less homeobox 5 (DLX5) and distal-less homeobox 6 (DLX6), identified a 2.1 kb LINE-1 insertion within DLX6 in CP1 NSDTRs. The LINE-1 insertion is predicted to insert a premature stop codon within the homeodomain of DLX6. This prompted the sequencing of DLX5 and DLX6 in a human cohort with CP, where a missense mutation within the highly conserved DLX5 homeobox of a patient with PRS was identified. This suggests the involvement of DLX5 in the development of PRS. These results demonstrate the power of the canine animal model as a genetically tractable approach to understanding naturally occurring craniofacial birth defects in humans.

Gene Frequency - genetics

Humans

Long Interspersed Nucleotide Elements - genetics

Cleft Palate - genetics

Genes, Homeobox - genetics

Homeodomain Proteins - genetics

Mutation, Missense - genetics

Phenotype

Animals

Pierre Robin Syndrome - genetics

Dogs

Polymorphism, Single Nucleotide - genetics

Genome-Wide Association Study - methods

Mandible - metabolism

Details

Title: Subtitle: A LINE-1 insertion in DLX6 is responsible for cleft palate and mandibular abnormalities in a canine model of Pierre Robin sequence
Creators: Zena T Wolf - Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, Davis, California, United States of America
Elizabeth J Leslie - Department of Pediatrics, University of Iowa, Iowa City, Iowa, United States of America
Boaz Arzi - Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, Davis, California, United States of America
Kartika Jayashankar - Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, Davis, California, United States of America
Nili Karmi - Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, Davis, California, United States of America
Zhonglin Jia - Department of Pediatrics, University of Iowa, Iowa City, Iowa, United States of America; State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China; Department of Cleft Lip and Palate Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China
Douglas J Rowland - Center for Molecular and Genomic Imaging, University of California, Davis, Davis, California, United States of America
Amy Young - Department of Animal Science, University of California, Davis, Davis, California, United States of America
Noa Safra - Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, Davis, California, United States of America
Saundra Sliskovic - Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, Davis, California, United States of America
Jeffrey C Murray - Department of Pediatrics, University of Iowa, Iowa City, Iowa, United States of America
Claire M Wade - Faculty of Veterinary Science, University of Sydney, Sydney, New South Wales, Australia
Danika L Bannasch - Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, Davis, California, United States of America
Resource Type: Journal article
Publication Details: PLoS genetics, Vol.10(4), pp.e1004257-e1004257
DOI: 10.1371/journal.pgen.1004257
PMID: 24699068
PMCID: PMC3974639
NLM abbreviation: PLoS Genet
ISSN: 1553-7390
eISSN: 1553-7404
Publisher: Public Library Science; United States
Grant note: T32 GM008629 / NIGMS NIH HHS R01DE08559 / NIDCR NIH HHS R01DE022532 / NIDCR NIH HHS U01 DE020057 / NIDCR NIH HHS R01 DE008559 / NIDCR NIH HHS R01 DE022532 / NIDCR NIH HHS
Language: English
Date published: 04/2014
Academic Unit: Anatomy and Cell Biology; Stead Family Department of Pediatrics; Epidemiology; Pediatric Dentistry; Craniofacial Anomalies Research Center; Dental Research
Record Identifier: 9984025413702771

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