OMIA:001758-9615 : Cataract, early onset, HSF4-related in Canis lupus familiaris (dog)

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:

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

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:

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


By default, variants are sorted chronologically by year of publication, to provide a historical perspective. Readers can re-sort on any column by clicking on the column header. Click it again to sort in a descending order. To create a multiple-field sort, hold down Shift while clicking on the second, third etc relevant column headers.

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 Year Published PubMed ID(s) Acknowledgements
456 Australian Shepherd (Dog) 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 Boston Terrier (Dog) Staffordshire Bull Terrier (Dog) 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

Cite this entry

Nicholas, F. W., Tammen, I., & Sydney Informatics Hub. (2024). OMIA:001758-9615: Online Mendelian Inheritance in Animals (OMIA) [dataset].


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.

2024 Moretti, R., Massimello, G., Chessa, S., Sartore, S., Tranchero, A., Profiti, M., Sacchi, P. :
Allele and genotype frequencies for primary hereditary cataract, multifocal retinopathy 1, and degenerative myelopathy in Pyrenean Mountain dog from Italy. Top Companion Anim Med 58:S1938-9736(23)00084-3:100844, 2024. Pubmed reference: 38081509. DOI: 10.1016/j.tcam.2023.100844.
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.
2021 Genetics Committee of the American College of Veterinary Opthalmologists :
The Blue Book: Ocular disorders presumed to be inherited in purebred dogs. 13th Edition , 2021.
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] J Vet Intern Med 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. DOI: 10.1111/j.1748-5827.1978.tb05463.x.
1976 Barnett, K.C. :
Comparative aspects of canine hereditary eye disease. Adv Vet Sci Comp Med 20:39-67, 1976. Pubmed reference: 827198.

Edit History

  • Created by Frank Nicholas on 05 Dec 2012
  • Changed by Frank Nicholas on 05 Dec 2012
  • Changed by Frank Nicholas on 23 Apr 2015
  • Changed by Frank Nicholas on 03 Oct 2019
  • Changed by Imke Tammen2 on 22 May 2022
  • Changed by Imke Tammen2 on 16 Jun 2023
  • Changed by Imke Tammen2 on 22 May 2024