OMIA 002551-9615 : Mitochondrial fission encephalopathy in Canis lupus familiaris
Cristen et al. (2022) reported that "Genotypes [at the MFF locus] in a cohort of four affected and 70 unaffected Bullmastiffs showed perfect [autosomal recessive] segregation with the disease phenotype. . . . All four available cases were homozygous mutant, one obligate carrier was heterozygous and none of the 70 unaffected dogs were homozygous for the mutant allele."Molecular basis: Cristen et al. (2022) reported that comparison of the whole-genome sequence of an affected Bullmastiff "with 782 control genomes of dogs from diverse breeds . . . revealed a private homozygous frameshift variant in the MFF gene in the affected dog, XM_038574000.1: c.471_475delinsCGCTCT, that is predicted to truncate 55% of the wild type MFF open reading frame, XP_038429928.1: p.(Glu158Alafs*14). Human patients with pathogenic MFF variants suffer from ‘encephalopathy due to defective mitochondrial and peroxisomal fission 2' ". Clinical features: Carmichael et al. (1983) provided the first clinical and pathological description of the disease. The most striking findings were ataxia, visual impairment and changes in behaviour. Cristen et al. (2022) "investigated two young Bullmastiffs showing similar clinical signs. They developed progressive gait and behavioural abnormalities with an onset at around 6 months of age. Neurological assessment was consistent with a multifocal brain disease. Magnetic resonance imaging of the brain showed intra-axial bilateral symmetrical focal lesions localised to the cerebellar nuclei. Based on the juvenile age, nature of neurological deficits and imaging findings, an inherited disorder of the brain was suspected." Pathology: Carmichael et al. (1983) reported "Macroscopically there was a moderate to severe internal hydrocephalus with dilation of all ventricles and the cerebral aqueduct. In addition a yellow/brown discoloration of the cerebellar nuclei was noted. The salient microscopic abnormality, a spongy vacuolar change with gliosis, was present in three deep cerebellar nuclei ... and a small localised area in the base of the inferior colliculus. ... Gliosis was present with an increase in both microglia and astrocytes, many of which were hypertrophied. Axonal spheroids were frequently observed within the lesions. ... The lesions were all bilaterally symmetrical."
Carmichael (1987) documented changes in the morphology of mitochondria of affected dogs by electron microscopy: "Mitochondria were increased in number and many bizarre forms were present."Prevalence: Cristen et al. (2022) reported that "The carrier frequency in the unrelated control cohort [of Bullmastiffs] was 12/65 (18%)". Breed: Bull Mastiff. Associated gene:
|Symbol||Description||Species||Chr||Location||OMIA gene details page||Other Links|
|MFF||mitochondrial fission factor||Canis lupus familiaris||25||NC_051829.1 (40359046..40389383)||MFF||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|
|1489||Bull Mastiff||Mitochondrial fission encephalopathy||MFF||delins, small (<=20)||Naturally occurring variant||UU_Cfam_GSD_1.0||25||g.40322999_40323003delinsCGCTCT||c.471_475delinsCGCTCT||p.(E158Afs*14)||XM_038574000.1; XP_038429928.1||2022||36085405|
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.
|2022||Christen, M., Gutierrez-Quintana, R., Vandenberghe, H., Kaczmarska, A., Penderis, J., José-López, R., Rupp, A., Griffiths, I.R., Jagannathan, V., Leeb, T. :|
|Mitochondrial fission factor (MFF) frameshift variant in Bullmastiffs with mitochondrial fission encephalopathy. Anim Genet :, 2022. Pubmed reference: 36085405. DOI: 10.1111/age.13263.|
|2001||Johnson, R.P., Neer, T.M., Partington, B.P., Cho, D.Y., Partington, C.R. :|
|Familial cerebellar ataxia with hydrocephalus in bull mastiffs. Vet Radiol Ultrasound 42:246-9, 2001. Pubmed reference: 11405268. DOI: 10.1111/j.1740-8261.2001.tb00934.x.|
|1987||Carmichael, S. :|
|Familial cerebellar ataxia in the Bull Mastiff. Master thesis, University of Glasgow Veterinary School :https://theses.gla.ac.uk/77525/1/10995573.pdf, 1987.|
|1983||Carmichael, S., Griffiths, I.R., Harvey, M.J. :|
|Familial cerebellar ataxia with hydrocephalus in bull mastiffs. Vet Rec 112:354-8, 1983. Pubmed reference: 6857976. DOI: 10.1136/vr.112.15.354.|
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