Canine models of human amelogenesis imperfecta: identification of novel recessive ENAM and ACP4 variants

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Hytönen , M K , Arumilli , M , Sarkiala , E , Nieminen , P & Lohi , H 2019 , ' Canine models of human amelogenesis imperfecta: identification of novel recessive ENAM and ACP 4 variants ' , Human Genetics , vol. 138 , no. 5 , pp. 525-533 .

Title: Canine models of human amelogenesis imperfecta: identification of novel recessive ENAM and ACP4 variants
Author: Hytönen, Marjo K.; Arumilli, Meharji; Sarkiala, Eva; Nieminen, Pekka; Lohi, Hannes
Contributor organization: Department of Medical and Clinical Genetics
Veterinary Genetics
Hannes Tapani Lohi / Principal Investigator
Veterinary Biosciences
STEMM - Stem Cells and Metabolism Research Program
University Management
Small Animal Hospital
Equine and Small Animal Medicine
Department of Oral and Maxillofacial Diseases
University of Helsinki
Research Programs Unit
Helsinki One Health (HOH)
Date: 2019-05
Language: eng
Number of pages: 9
Belongs to series: Human Genetics
ISSN: 1432-1203
Abstract: Amelogenesis imperfecta (AI) refers to a genetically and clinically heterogeneous group of inherited disorders affecting the structure, composition, and quantity of tooth enamel. Both non-syndromic and syndromic forms of AI have been described and several genes affecting various aspects of the enamel physiology have been reported. Genetically modified murine models of various genes have provided insights into the complex regulation of proper amelogenesis. Non-syndromic AI occurs spontaneously also in dogs with known recessive variants in ENAM and SLC24A4 genes. Unlike rodents with a reduced dentition and continuously erupting incisors, canine models are valuable for human AI due to similarity in the dental anatomy including deciduous and permanent teeth. We have performed a series of clinical and genetic analyses to investigate AI in several breeds of dogs and describe here two novel recessive variants in the ENAM and ACP4 genes. A fully segregating missense variant (c.716C>T) in exon 8 of ENAM substitutes a well-conserved proline to leucine, p.(Pro239Leu), resulting in a clinical hypomineralization of teeth. A 1-bp insertion in ACP4 (c.1189dupG) is predicted to lead to a frameshift, p.(Ala397Glyfs), resulting in an abnormal C-terminal part of the protein, and hypoplastic AI. The ENAM variant was specific for Parson Russell Terriers with a carrier frequency of 9%. The ACP4 variant was found in two breeds, Akita and American Akita with a carrier frequency of 22%. These genetic findings establish novel canine models of human AI with a particular interest in the case of the ACP4-deficient model, since ACP4 physiology is poorly characterized in human AI. The affected dogs could also serve as preclinical models for novel treatments while the breeds would benefit from genetic tests devised here for veterinary diagnostics and breeding programs.
Subject: DEFECTS
1184 Genetics, developmental biology, physiology
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion

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