A structural UGDH variant associated with standard Munchkin cats

Abstract

Background: Munchkin cats were founded on a naturally occurring mutation segregating into long-legged and short-legged types. Short-legged cats showed disproportionate dwarfism (chondrodysplasia) in which all four legs are short and are referred as standard Munchkin cats. Long-legged animals are referred as non-standard Munchkin cats. A previous study using genome-wide single nucleotide polymorphisms (SNPs) for genome-wide association analysis identified a significantly associated region at 168-184 Mb on feline chromosome (FCA) B1.

Results: In this study, we validated the critical region on FCA B1 using a case-control study with 89 cats and 14 FCA B1-SNPs. A structural variant within UGDH (NC_018726.2:g.173294289_173297592delins108, Felis catus 8.0, equivalent to NC_018726.3:g.174882895_174886198delins108, Felis catus 9.0) on FCA B1 was perfectly associated with the phenotype of short-legged standard Munchkin cats.

Conclusion: This UGDH structural variant very likely causes the chondrodysplastic (standard) phenotype in Munchkin cats. The lack of homozygous mutant phenotypes and reduced litter sizes in standard Munchkin cats suggest an autosomal recessive lethal trait in the homozygote state. We propose an autosomal dominant mode of inheritance for the chondrodysplastic condition in Munchkin cats.

Keywords: Cat; Chondrodysplasia; Felis catus; Munchkin; UGDH; Whole genome sequencing.

Fig. 1

Munchkin cat phenotype. a Lateral view of the 4-year old standard Munchkin cat sire. Note the head is proportional to the body but the legs are shortened. b Frontal view of the kittens from litter A showing two male standard Munchkin kittens (right) and one female non-standard Munchkin full sibling (left)

Fig. 2

Computed tomography of a 4-year old standard Munchkin cat sire and an adult female domestic cat control. Lateral view of a standard Munchkin cat (a, c, e) and a domestic cat (b, d, f). The limbs of the standard Munchkin cat are shortened in relation to the body. The fore limbs of the standard Munchkin cat (c) show a shortening of all distal and proximal long bones and higher diaphyseal diameters, particularly of humerus, compared to the fore limbs of domestic cat (d). The hind limbs (e, f) also show higher diaphyseal diameters in particular in the femur as well as a shortening of the long bones

Fig. 3

Schematic representation of cDNA in wild type (wt) and standard Munchkin cats (sMc) for PCR-type 1. PCR across the deletion from (a) exon 10 (ENSFCAT00000009602.6) or (b) exon 9 (ENSFCAT00000055794.2) to the 3′-UTR (non-deleted region) showed a 493 bp amplicon. Sanger sequencing of this 493 bp amplicon showed that the 108 bp insert is not transcribed but this PCR-product consists of 73 bp of the exon 10 (ENSFCAT00000009602.6) or exon 9 (ENSFCAT00000055794.2), plus a partially retained intron 10–11 (ENSFCAT00000009602.6) or intron 9–10 (ENSFCAT00000055794.2) of 309 bp and 115 bp of the 3’UTR