Mitochondrial fission factor (MFF) frameshift variant in Bullmastiffs with mitochondrial fission encephalopathy.

Christen, Matthias; Gutierrez-Quintana, Rodrigo; Vandenberghe, Helene; Kaczmarska, Adriana; Penderis, Jacques; José-López, Roberto; Rupp, Angie; Griffiths, Ian R; Jagannathan, Vidhya; Leeb, Tosso (2022). Mitochondrial fission factor (MFF) frameshift variant in Bullmastiffs with mitochondrial fission encephalopathy. Animal genetics, 53(6), pp. 814-820. Wiley 10.1111/age.13263

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Familial cerebellar ataxia with hydrocephalus in Bullmastiffs was described almost 40 years ago as a monogenic autosomal recessive trait. We 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. We sequenced the genome of one affected Bullmastiff. The data were compared with 782 control genomes of dogs from diverse breeds. This search 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'. Archived samples from two additional affected Bullmastiffs related to the originally described cases were obtained. Genotypes in a cohort of four affected and 70 unaffected Bullmastiffs showed perfect segregation with the disease phenotype. The available data together with information from previous disease reports allow classification of the investigated MFF frameshift variant as pathogenic and probably causative defect of the observed neurological phenotype. In analogy to the human phenotype, we propose to rename this disease 'mitochondrial fission encephalopathy (MFE)'.

Item Type:

Journal Article (Original Article)

Division/Institute:

09 Interdisciplinary Units > Next Generation Sequencing (NGS) Platform
05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH) > Institute of Genetics
05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH)

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Christen, Matthias (A), Jagannathan, Vidya, Leeb, Tosso

Subjects:

500 Science > 570 Life sciences; biology
500 Science > 590 Animals (Zoology)
600 Technology > 610 Medicine & health

ISSN:

1365-2052

Publisher:

Wiley

Language:

English

Submitter:

Pubmed Import

Date Deposited:

12 Sep 2022 13:46

Last Modified:

02 Mar 2023 23:36

Publisher DOI:

10.1111/age.13263

PubMed ID:

36085405

Uncontrolled Keywords:

Canis lupus familiaris animal model dog mitochondrion neurology precision medicine veterinary medicine

BORIS DOI:

10.48350/172845

URI:

https://boris.unibe.ch/id/eprint/172845

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