OMIA:001758-9615 : Cataract, early onset, HSF4-related in Canis lupus familiaris
Categories: Vision / eye phene
Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 116800 (trait) , 602438 (gene)
Links to MONDO diseases:
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) 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, Boston Terrier, Staffordshire Bull Terrier.
|Symbol||Description||Species||Chr||Location||OMIA gene details page||Other Links|
|HSF4||heat shock transcription factor 4||Canis lupus familiaris||5||NC_051809.1 (82635528..82626129)||HSF4||Homologene, Ensembl , NCBI gene|
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WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.
Since October 2021, OMIA includes a semiautomated lift-over pipeline to facilitate updates of genomic positions to a recent reference genome position. These changes to genomic positions are not always reflected in the ‘acknowledgements’ or ‘verbal description’ fields in this table.
|OMIA Variant ID||Breed(s)||Variant Phenotype||Gene||Allele||Type of Variant||Source of Genetic Variant||Reference Sequence||Chr.||g. or m.||c. or n.||p.||Verbal Description||EVA ID||Inferred EVA rsID||Year Published||PubMed ID(s)||Acknowledgements|
|456||Australian Shepherd||Cataract, early onset||HSF4||deletion, small (<=20)||Naturally occurring variant||CanFam3.1||5||g.82198114del||c.971del||p.(P324Hfs*87)||NM_001048121.1; NP_001041586.1; published as g.85286582delC||2006||16939467|
|568||Staffordshire Bull Terrier||Cataract, early onset||HSF4||insertion, small (<=20)||Naturally occurring variant||CanFam3.1||5||g.82198114_82198115insG||c.971_972insC||p.(L325Tfs*28)||NM_001048121.1; NP_001041586.1; published as g.85286582_85286583insC||2006||16939467|
Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
|2023||Majchrakova, Z., Hrckova Turnova, E., Bielikova, M., Turna, J., Dudas, A. :|
|The incidence of genetic disease alleles in Australian Shepherd dog breed in European countries. PLoS One 18:e0281215, 2023. Pubmed reference: 36848350 . DOI: 10.1371/journal.pone.0281215.|
|2019||Lewis, T.W., Mellersh, C.S. :|
|Changes in mutation frequency of eight Mendelian inherited disorders in eight pedigree dog populations following introduction of a commercial DNA test. PLoS One 14:e0209864, 2019. Pubmed reference: 30650096 . DOI: 10.1371/journal.pone.0209864.|
|2015||Ricketts, S.L., Pettitt, L., McLaughlin, B., Jenkins, C.A., Mellersh, C.S. :|
|A novel locus on canine chromosome 13 is associated with cataract in the Australian Shepherd breed of domestic dog. Mamm Genome 26:257-263, 2015. Pubmed reference: 25894238 . DOI: 10.1007/s00335-015-9562-2.|
|2013||Bellumori, T.P., Famula, T.R., Bannasch, D.L., Belanger, J.M., Oberbauer, A.M. :|
|Prevalence of inherited disorders among mixed-breed and purebred dogs: 27,254 cases (1995-2010). J Am Vet Med Assoc 242:1549-55, 2013. Pubmed reference: 23683021 . DOI: 10.2460/javma.242.11.1549.|
|2009||Mellersh, CS., Mclaughlin, B., Ahonen, S., Pettitt, L., Lohi, H., Barnett, KC. :|
|Mutation in HSF4 is associated with hereditary cataract in the Australian Shepherd. Vet Ophthalmol 12:372-8, 2009. Pubmed reference: 19883468 . DOI: 10.1111/j.1463-5224.2009.00735.x.|
|2008||Müller, C., Wöhlke, A., Distl, O. :|
|Evaluation of canine heat shock transcription factor 4 (HSF4) as a candidate gene for primary cataracts in the Dachshund and the Entlebucher Mountain dog. Vet Ophthalmol 11:34-7, 2008. Pubmed reference: 18190350 . DOI: 10.1111/j.1463-5224.2007.00598.x.|
|Oberbauer, AM., Hollingsworth, SR., Belanger, JM., Regan, KR., Famula, TR. :|
|Inheritance of cataracts and primary lens luxation in Jack Russell Terriers. Am J Vet Res 69:222-7, 2008. Pubmed reference: 18241019 . DOI: 10.2460/ajvr.69.2.222.|
|2007||Engelhardt, A., Wöhlke, A., Distl, O. :|
|Evaluation of canine heat-shock transcription factor 4 as a candidate for primary cataracts in English Cocker Spaniels and wire-haired Kromfohrlanders. J Anim Breed Genet 124:242-5, 2007. Pubmed reference: 17651328 . DOI: 10.1111/j.1439-0388.2007.00663.x.|
|Mellersh, CS., Graves, KT., Mclaughlin, B., Ennis, RB., Pettitt, L., Vaudin, M., Barnett, KC. :|
|Mutation in HSF4 associated with early but not late-onset hereditary cataract in the Boston Terrier. J Hered 98:531-3, 2007. Pubmed reference: 17611257 . DOI: 10.1093/jhered/esm043.|
|2006||Mellersh, CS., Pettitt, L., Forman, OP., Vaudin, M., Barnett, KC. :|
|Identification of mutations in HSF4 in dogs of three different breeds with hereditary cataracts. Vet Ophthalmol 9:369-78, 2006. Pubmed reference: 16939467 . DOI: 10.1111/j.1463-5224.2006.00496.x.|
|2000||Patterson, D.F. :|
|Companion animal medicine in the age of medical genetics [Review] Journal of Veterinary Internal Medicine 14:1-9, 2000. Pubmed reference: 10668810 .|
|1978||Barnett, KC. :|
|Hereditary cataract in the dog. J Small Anim Pract 19:109-20, 1978. Pubmed reference: 642468 .|
|1976||Barnett, K.C. :|
|Comparative aspects of canine hereditary eye disease. Adv Vet Sci Comp Med 20:39-67, 1976. Pubmed reference: 827198 .|
- Created by Frank Nicholas on 05 Dec 2012
- Changed by Frank Nicholas on 05 Dec 2012
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