Categories: Vision / eye phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 116800 (trait) , 602438 (gene)

Links to relevant human diseases in MONDO:

• MONDO:0007290: cataract 5 multiple types

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2006

Species-specific name: Primary hereditary cataract

Species-specific symbol: PHC

Species-specific description: Other forms of inherited cataract have been been described in other breeds, for examples see 'OMIA:002536-9615 - Cataract, FYCO1-related' and 'OMIA:000168-9615 -Cataract, generic'.

Inheritance: Barnett (1978) reported single-locus autosomal recessive inheritance. The mode of inheritance is reported as 'co-dominant' in Australian shepherds: "Dogs with one copy of the mutation develop bilateral posterior cataracts and homozygotes develop a nuclear cataract that typically progresses to a mature cataract" (Genetics Committee of the American College of Veterinary Opthalmologists, 2021).

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) and Oberbauer et al. (2008) drew the same conclusion for primary cataract in Dachshunds, Entlebucher Mountain dogs and Jack Russell terriers. Mellersh et al. (2009) confirmed the Australian Shepherd mutation but also reported that other mutations are also likely to be involved.

Clinical features: Cataract, defined as opacity of the lens, can be hereditary or nonhereditary. Clinical features include change in eye colour, pupil size, alteration in vision. Patients may be less aware of their surroundings due to reduced vision. In severe cataract cases, glaucoma can develop, causing pain and discomfort to the patient. Heritable cataracts are often categorised by marked breed specificity, age of onset, rate of progression, and the degree of bilateral symmetry (Mellersh et al., 2006). Mellersh et al. (2006) "Primary HC in the Staffordshire Bull Terrier was first reported in the UK in 1976 [Barnett, 1978]. This cataract is bilateral, symmetrical in the two eyes, and progressive until total with resultant blindness [Patterson, 2000]. It is not congenital but appears at a few weeks to months in age, progressing to total by 2 to 3 years of age. The ophthalmoscopic and slit-lamp biomicroscopic appearance is of a central area of opacity with a number of small areas of denser opacity ... , initially with a clear cortex. Progression is bilaterally symmetrical, the cataract becoming mature between 2 and 3 years ... ." [IT thanks DVM student Stephanie Chan for contributions to this entry in April 2022.]

Breeds: Australian Shepherd (Dog) (VBO_0200095), Boston Terrier (Dog) (VBO_0200204), French Bulldog (Dog) (VBO_0201455), Miniature Pinscher (Dog) (VBO_0200893), Staffordshire Bull Terrier (Dog) (VBO_0201296).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: