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

Research output: Contribution to journalArticle

27 Citations (Scopus)

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; praw = 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.

Original languageEnglish (US)
Article numbere1004257
JournalPLoS Genetics
Volume10
Issue number4
DOIs
StatePublished - 2014

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Pierre Robin Syndrome
cleft palate
Homeobox Genes
Cleft Palate
abnormality
defect
Canidae
dogs
Nova Scotia
ducks
Ducks
tomography
phenotype
chromosome
mutation
genome
micro-computed tomography
missense mutation
homeotic genes
stop codon

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)
  • Medicine(all)

Cite this

A LINE-1 Insertion in DLX6 Is Responsible for Cleft Palate and Mandibular Abnormalities in a Canine Model of Pierre Robin Sequence. / Wolf, Zena T.; Leslie, Elizabeth J.; Arzi, Boaz; Jayashankar, Kartika; Karmi, Nili; Jia, Zhonglin; Rowland, Douglas J.; Young, Amy; Safra, Noa; Sliskovic, Saundra; Murray, Jeffrey C.; Wade, Claire M.; Bannasch, Danika L.

In: PLoS Genetics, Vol. 10, No. 4, e1004257, 2014.

Research output: Contribution to journalArticle

Wolf, ZT, Leslie, EJ, Arzi, B, Jayashankar, K, Karmi, N, Jia, Z, Rowland, DJ, Young, A, Safra, N, Sliskovic, S, Murray, JC, Wade, CM & Bannasch, DL 2014, 'A LINE-1 Insertion in DLX6 Is Responsible for Cleft Palate and Mandibular Abnormalities in a Canine Model of Pierre Robin Sequence', PLoS Genetics, vol. 10, no. 4, e1004257. https://doi.org/10.1371/journal.pgen.1004257
Wolf, Zena T. ; Leslie, Elizabeth J. ; Arzi, Boaz ; Jayashankar, Kartika ; Karmi, Nili ; Jia, Zhonglin ; Rowland, Douglas J. ; Young, Amy ; Safra, Noa ; Sliskovic, Saundra ; Murray, Jeffrey C. ; Wade, Claire M. ; Bannasch, Danika L. / A LINE-1 Insertion in DLX6 Is Responsible for Cleft Palate and Mandibular Abnormalities in a Canine Model of Pierre Robin Sequence. In: PLoS Genetics. 2014 ; Vol. 10, No. 4.
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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; praw = 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.",
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