OMIA:002374-9913 : Charcot Marie Tooth disease, FGD4-related in Bos taurus (taurine cattle)
Categories: Nervous system phene
Links to MONDO diseases: No links.
Mendelian trait/disorder: yes
Mode of inheritance: Autosomal recessive
Considered a defect: yes
Key variant known: yes
Year key variant first reported: 2021
Mapping: Reynolds et al. (2021) “report one of the largest sequence-resolution screens of cattle to date, targeting discovery and validation of non-additive effects in 130,725 animals. We highlight six novel recessive loci with impacts [on body weight, stature or body condition score] generally exceeding the largest-effect variants identified from additive genome-wide association studies … [and] detail six novel putative causative mutations with effects ranging from mild (3.5% reduction in body weight) to severe (>25% reduction in body weight and increased early-life mortality)." The authors "detected a significant locus for bodyweight on bovine chromosome 5 at 77.6 Mbp. This signal was represented by a single, significant variant at the locus, representing a non-sense mutation in the FYVE, RhoGEF and PH domain containing 4 gene (FGD4 ....), a gene for which non-sense variants in humans have been proposed to underlie Charcot Marie Tooth disease (CMT)."
Molecular basis: Reynolds et al. (2021) report a FGD4 c.1671+1G>A splice donor mutation in New Zealand dairy cattle as likely causal variant for the the bodyweight QTL and Charcot Marie Tooth disease.
Have human generated variants been created, e.g. through genetic engineering and gene editing
Clinical features: Reynolds et al. (2021) “conducted a genotypic screen of 568 animals to identify calves homozygous for the FGD4 (and other) mutations. … Nine of these homozygous mutant animals were then recruited for the farm trial… . Growth rates of FGD4 homozygotes were significantly reduced …, with the bodyweight difference between these animals and controls widening to 49.7kg by 24 months of age … . At the end of the farm trial (~27 months of age), FGD4 mutant animals subjectively demonstrated behavioural differences and instances of loss of motor control. In these cases, routine animal handling procedures such as confinement in a cattle crush and head bail appeared to lead to increased restlessness and agitation in FGD4 mutant animals, with some animals collapsing to a ‘kneeling’ position – a behaviour not observed in controls ... .”
Pathology: Histopathological findings of peripheral nerves from FGD4 homozygotes included hypercellularity, Schwann cell hyperplasia, axonal swelling and degeneration, and lack of myelin staining consistent with demyelination (Reynolds et al., 2021).
Prevalence: The alternative allele frequency in New Zealand dairy cattle was reported as 0.039 in Holstein Friesian cattle, 0.001 in Jersey cattle and 0.024 in the 25,239 dairy cattle genotyped (Reynolds et al., 2021).
Holstein Friesian (Cattle) (VBO_0000239),
Jersey (Cattle) (VBO_0000250).
Breeds in which the phene has been documented. For breeds in which a likely causal variant has been documented, see the variant table below
|Symbol||Description||Species||Chr||Location||OMIA gene details page||Other Links|
|FGD4||FYVE, RhoGEF and PH domain containing 4||Bos taurus||5||NC_037332.1 (77463045..77219366)||FGD4||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|
|1326||Holstein Friesian (Cattle) Jersey (Cattle)||Charcot Marie Tooth disease||FGD4||splicing||Naturally occurring variant||ARS-UCD1.2||5||g.77262490C>T||c.1671+1G>A||Splice donor mutation based on XM_005206883.3||2021||34045765|
Cite this entry
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||Dittmer, K.E., Neeley, C., Perrott, M.R., Reynolds, E., Garrick, D.J., Littlejohn, M.D. :|
|Pathology of the peripheral neuropathy Charcot-Marie-Tooth disease type 4H in Holstein Friesian cattle with a splice site mutation in FGD4. Vet Pathol 59:442-450, 2022. Pubmed reference: 35300540. DOI: 10.1177/03009858221083041.|
|2021||Reynolds, E.G.M., Neeley, C., Lopdell, T.J., Keehan, M., Dittmer, K., Harland, C.S., Couldrey, C., Johnson, T.J.J., Tiplady, K., Worth, G., Walker, M., Davis, S.R., Sherlock, R.G., Carnie, K., Harris, B.L., Charlier, C., Georges, M., Spelman, R.J., Garrick, D.J., Littlejohn, M.D. :|
|Non-additive association analysis using proxy phenotypes identifies novel cattle syndromes. Nat Genet 53:949-54, 2021. Pubmed reference: 34045765. DOI: 10.1038/s41588-021-00872-5.|
- Created by Imke Tammen2 on 09 Aug 2021
- Changed by Imke Tammen2 on 09 Aug 2021