Aristaless-Like Homeobox protein 1 (ALX1) variant associated with craniofacial structure and frontonasal dysplasia in Burmese cats

Leslie A Lyons 1, Carolyn A Erdman 2, Robert A Grahn 3, Michael J Hamilton 4, Michael J Carter 5, Christopher R Helps 6, Hasan Alhaddad 7, Barbara Gandolfi 8

Affiliations

15 January 2016

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doi: 10.1016/j.ydbio.2015.11.015

Abstract

Frontonasal dysplasia (FND) can have severe presentations that are medically and socially debilitating. Several genes are implicated in FND conditions, including Aristaless-Like Homeobox 1 (ALX1), which is associated with FND3. Breeds of cats are selected and bred for extremes in craniofacial morphologies. In particular, a lineage of Burmese cats with severe brachycephyla is extremely popular and is termed Contemporary Burmese. Genetic studies demonstrated that the brachycephyla of the Contemporary Burmese is a simple co-dominant trait, however, the homozygous cats have a severe craniofacial defect that is incompatible with life. The craniofacial defect of the Burmese was genetically analyzed over a 20 year period, using various genetic analysis techniques. Family-based linkage analysis localized the trait to cat chromosome B4. Genome-wide association studies and other genetic analyses of SNP data refined a critical region. Sequence analysis identified a 12bp in frame deletion in ALX1, c.496delCTCTCAGGACTG, which is 100% concordant with the craniofacial defect and not found in cats not related to the Contemporary Burmese.

Keywords: CART1; Cartilage homeo protein 1; Domestic cat; FND; Facial development; Felis silvestris catus; Frontonasal dysplasia.

Figures

Figure 1 Variation of the Burmese cat breed’s craniofacial structure. A) Traditional lines are not as extreme, but selection has continued for the past 30 years for a more extreme type that is not associated with congenital abnormalities. Some Traditional lines and contemporary lines are now difficult to distinguish phenotypically. Thus, all Burmese need to be genotyped to confirm presence or absence of the variant. B) The Contemporary style Burmese has extreme brachycephyla and the phenotype is association with the craniofacial defect. C) Frontal view displays duplication of the maxillary processes and agenesis of the medial nasal prominence. D) Lateral view displays abnormal development of the maxillary processes and ocular degeneration. Photographs courtesy of Nancy Reeves, Isabelle Marchand and Richard Katris – Chanan Photography.

Figure 1 Variation of the Burmese cat breed’s craniofacial structure. A) Traditional lines are not as extreme, but selection has continued for the past 30 years for a more extreme type that is not associated with congenital abnormalities. Some Traditional lines and contemporary lines are now difficult to distinguish phenotypically. Thus, all Burmese need to be genotyped to confirm presence or absence of the variant. B) The Contemporary style Burmese has extreme brachycephyla and the phenotype is association with the craniofacial defect. C) Frontal view displays duplication of the maxillary processes and agenesis of the medial nasal prominence. D) Lateral view displays abnormal development of the maxillary processes and ocular degeneration. Photographs courtesy of Nancy Reeves, Isabelle Marchand and Richard Katris – Chanan Photography.

Figure 2. Manhattan plot of the Burmese head deformity GWAS and SNPs genotypes within chromosome B4 haplotype a. The plot represents the Praw (top) and Pgenome (bottom) values of each SNP included in the case-control association study. The association study compared the affected Burmese and Bombay cats. A significant association with chromosome B4 was detected. b. The area from SNP B4.121572441 (position 106,142,990) to SNP B4.114551707 (position 114,551,707) spans ~ 8.4 Mb. The two red vertical dashed lines represent the region of the single haplotype containing ALX1, from SNP B4.126353636 (position 110,094,604) to SNP B4.126530474 (position 110,255,914) spanning 161 Kb. Each SNP is represented by two squares where markers are on the x-axis and individuals on the y-axis. Gray boxes represent the major allele in the cases and black squares represent the minor.

Figure 2. Manhattan plot of the Burmese head deformity GWAS and SNPs genotypes within chromosome B4 haplotype a. The plot represents the Praw (top) and Pgenome (bottom) values of each SNP included in the case-control association study. The association study compared the affected Burmese and Bombay cats. A significant association with chromosome B4 was detected. b. The area from SNP B4.121572441 (position 106,142,990) to SNP B4.114551707 (position 114,551,707) spans ~ 8.4 Mb. The two red vertical dashed lines represent the region of the single haplotype containing ALX1, from SNP B4.126353636 (position 110,094,604) to SNP B4.126530474 (position 110,255,914) spanning 161 Kb. Each SNP is represented by two squares where markers are on the x-axis and individuals on the y-axis. Gray boxes represent the major allele in the cases and black squares represent the minor.

Figure 3 Three dimensional CT reconstructions of Burmese cat crania. Top) Frontal views of normal stillborn littermate of a Burmese with the craniofacial defect. Bottom) Lateral and dorsal-ventral view of Burmese kitten with a craniofacial defect. Normal kittens may carry the ALX1 variant. Affected kittens are homozygous for the variant and have the hallmark features of FND.

Figure 3 Three dimensional CT reconstructions of Burmese cat crania. Top) Frontal views of normal stillborn littermate of a Burmese with the craniofacial defect. Bottom) Lateral and dorsal-ventral view of Burmese kitten with a craniofacial defect. Normal kittens may carry the ALX1 variant. Affected kittens are homozygous for the variant and have the hallmark features of FND.

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