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This puppy is a Nova Scotia Duck Tolling Retriever, the breed with
discovered genetic mutation for cleft palate. (Imaage - Danika Bannasch/UC Davis)
G. 3D reconstruction of microCT imaging of CP1 and WT skulls with mandibles removed.
CP1 skull shows abnormally shaped palatine process and palatine bones.
Bones colored blue are the palatine processes and palatine bones.
WT skull shows anatomical location of normal palatine sutures
and shape of palatine processes and palatine bones.
H. 3D reconstruction of mandibles depicting abnormal angulation
of the condylar process (*) in CP1 mandibles compared to WT mandibles.
Image credit: PLOS Genetics, DOI: 10.1371/journal.pgen.1004257
Dog cleft palate aids understanding of birth defect
University of California at Davis School of Veterinary Medicine researchers have identified the genetic mutation responsible for a form of cleft palate in the dog breed Nova Scotia Duck Tolling Retrievers.
They hope that the discovery, which is the first dog model for the craniofacial defect, will lead to a better understanding of cleft palate in humans. Although cleft palate is one of the most common birth defects in children, affecting approximately one in 1,500 live human births in the United States, it is not completely understood.
The findings appear online in the journal PLOS Genetics.
“This discovery provides novel insight into the genetic cause of a form of cleft palate through the use of a less conventional animal model,” said Professor Danika Bannasch, a veterinary geneticist who led the study. “It also demonstrates that dogs have multiple genetic causes of cleft palate that we anticipate will help in the identification of additional candidate genes relevant to human cleft palate.”
Bannasch, who holds the Maxine Adler endowed chair in genetics, explains that common breeding practices have made the dog a unique animal model to help understand the genetic basis of naturally occurring birth defects.
Cleft palate occurs when there is a failure in the formation of the secondary palate, which makes up all of the soft palate as well as the majority of the hard palate.
Disrupting the sequential steps of palate development causes a cleft palate and leads to the spectrum of cases observed. Children born with cleft palate may develop hearing loss and difficulties with speech and eating. They can also be at increased risk for neurological deficits.
By conducting a genome-wide study of these particular retrievers with a naturally occurring cleft palate, researchers identified the gene mutation in the breed.
Dogs with this mutation also have a shortened lower jaw, similar to humans who have Pierre Robin Sequence. The disorder, a subset of cleft palate, affects one in 8,500 live human births and is characterized by a cleft palate, shortened lower jaw and displacement of the base of the tongue.
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.
Cleft palate is one of the most commonly occurring birth defects in children, and yet its cause is not completely understood. In order to better understand cleft palate we have turned to man's best friend, the domestic dog. Common breeding practices have made the dog a unique animal model to help understand the genetic basis of naturally occurring birth defects. A genome-wide association study of Nova Scotia Duck Tolling Retrievers with naturally occurring cleft palate led to the investigation of two homeobox genes, DLX5 and DLX6. Dogs with this mutation also have a shortened lower jaw, which resembles those who have Pierre Robin Sequence (PRS). Investigation into people with PRS identifies a mutation within a highly conserved and functional region of DLX5 that may contribute to the development of PRS. This exemplifies how the dog will help us better understand common birth defects.
Additional UC Davis researchers include: Zena T. Wolf, a graduate student in the Department of Population Health and Reproduction at the School of Veterinary Medicine, whose thesis topic is the study of craniofacial clefts in dogs; and Assistant Professor Boaz Arzi from the Department of Surgical and Radiological Sciences, School of Veterinary Medicine.
Funding was provided by the Center for Companion Animal Health at the School of Veterinary Medicine and the National Institutes of Health.
About UC Davis
For more than 100 years, UC Davis has been one place where people are bettering humanity and our natural world while seeking solutions to some of our most pressing challenges. Located near the state capital, UC Davis has more than 33,000 students, over 2,500 faculty and more than 21,000 staff, an annual research budget of over $750 million, a comprehensive health system and 13 specialized research centers. The university offers interdisciplinary graduate study and more than 100 undergraduate majors in four colleges — Agricultural and Environmental Sciences, Biological Sciences, Engineering, and Letters and Science. It also houses six professional schools — Education, Law, Management, Medicine, Veterinary Medicine and the Betty Irene Moore School of Nursing.
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