Charcot-Marie-Tooth disease

Gene: FGD4

Transmission: Autosomal recessive

For an autosomal recessive genetic disease an animal must have two copies of the mutation in question to be at risk of developing the disease. Both parents of an affected animal must be carriers of at least one copy of the mutation. Animals that have only one copy of the mutation are not at risk of developing the disease but are carrier animals that can pass the mutation on to future generations.

Mutation: Substitution, FGD4 gene (splicing error) ; c.1671+1 G>A, chr.5.

Medical systems: Neurological

Breeds: Holstein-Friesian, Jersey

Age of onset of symptoms: Evident after 2 years.

A large phenotype-genotype association study was performed on over 130 thousand New Zealand dairy cows and a QTL (quantitative trait locus) on chromosome 5 was found to correlate with body weight.  Further studies identified a splice site mutation within the FGD4 gene as being responsible for the phenotype.  Double mutant animals showed significant weight reductions at two years of age, as well as some loss of motor control and increased restlessness and agitation compared to control animals. The FGD4 gene encodes a protein that is involved in regulating the actin cytoskeleton to confer proper cell shape.  Mutations in the FGD4 gene in humans can be responsible for the motor and sensory neuropathy named Charcot-Marie-Tooth (CMT) disease.  Histological evaluation of peripheral nerves of affected cattle showed Schwann cell hyperplasia, demyelination, axon swelling and axon degeneration, consistent with a CMT diagnosis.  The frequency of carrier animals (M/N) in the New Zealand Holstein population was measured to be 7.5% while in the Jersey population to be 4.7%.  DNA testing will now allow producers to identify carrier animals to eliminate this disease and this mutation from their animals via selective breeding.

References:

OMIA link: [2374-9913]

Dittmer KE, Neeley C, Perrott MR, et al. (2022) 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(3):442–450. [pm/35300540]

Reynolds EGM, Neeley C, Lopdell TJ, et al. (2021) Non-additive association analysis using proxy phenotypes identifies novel cattle syndromes. Nat Genet 53(7):949–954. [pm/34045765].

Contributed by: Mélissa Gendron and Mariane Robinson, Class of 2028, Faculty of Veterinary Medicine, University of Montreal.  (Translation, DWS)