Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 116800 (trait) , 602438 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2006

Species-specific name: Primary hereditary cataract

Species-specific symbol: PHC

Inheritance: Barnett (1978) reported single-locus autosomal recessive inheritance.

Mapping: Using sequence data from the initial canine genome assembly (Lindblad-Toh K, Wade CM, Mikkelsen TS et al. Nature 2005; 438: 803–819), Mellersch et al. (2006) identified microsatellite markers "adjacent to and flanking" each of 20 comparative candidate genes (based on known causative mutations in humans and mice). Association analysis with this disorder was conducted within each of the breeds Staffordshire Bull Terriers, American Cocker Spaniels, Golden Retrievers and Miniature Schnauzers. The only association was with markers flanking the gene HSF4 on chromosome CFA5 in Staffordshire Bull Terriers.

Ricketts et al. (2015) mapped a second locus in Australian Shepherd dogs to a 14.16 Mb region on chromosome CFA13 at 46.4 Mb

Molecular basis: Building on their mapping results (see above), Mellersh et al. (2006) sequenced the HSF4 gene in Staffordshire Bull Terriers segregating the disorder, and identified "a single C nucleotide insertion in exon 9 (CFA5 g85286582–85286583insC) that alters the reading frame of the gene and introduces a premature stop codon". The same mutation appears to be causative in Boston Terriers, and a different mutation in the same gene appears to be causative in Australian Shepherds: "a deletion of a C nucleotide at the same position of exon 9 in the affected Australian Shepherds (in which the disorder is autosomal dominant, unlike in the other two breeds, where it is autosomal recessive) (g.85286582delC) . . . , which is also predicted to alter the frame of the gene and introduce a premature stop codon, 177 nucleotides (59 amino acids) further downstream from that introduced by the deletion". Finally, the authors showed that neither of these mutations is causative in American Cocker Spaniels and Golden Retrievers. The following year, Mellersh et al. (2007) showed that late-onset cataract in Boston Terriers is not due to any mutation in HSF4. Engelhardt et al. (2007) showed that HSF4 mutations are not causative for primary cataract in English Cocker Spaniels and Wire-haired Kromfohrlanders. Müller et al. (2008) drew the same conclusion for primary cataract in Dachshunds and Entlebucher Mountain dogs. Mellersh et al. (2009) confirmed the Australian Shepherd mutation but also reported that other mutations are also likely to be involved.

Breeds: Australian Shepherd, Boston Terrier, Staffordshire Bull Terrier.

Associated gene: