Categories: Skeleton phene (incl. short stature & teeth)

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 602090 (gene) , 601216 (trait) , 617809 (trait)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2021

Species-specific name: Complex skeletal dysplasia

Species-specific description: In addition to the skeletal changes, LTBP3-related skeletal dysplasia is characterized by secondary neurological defects due to malformation of the vertebrae and compression of the spinal cord.

Molecular basis: Rudd Garces et al. (2021) "investigated a highly inbred family of British Shorthair cats in which two offspring were affected by deteriorating paraparesis due to complex skeletal malformations. ... The pedigree suggested monogenic autosomal recessive inheritance of the trait." The authors "sequenced the genome of an affected kitten and compared the data to 62 control genomes. This search yielded 55 private protein-changing variants of which only one was located in a likely functional candidate gene, LTBP3, encoding latent transforming growth factor β binding protein 3. This variant, c.158delG or p.(Gly53Alafs*16), represents a 1 bp frameshift deletion predicted to truncate 95% of the open reading frame. LTBP3 is a known key regulator of transforming growth factor β (TGF-β) and is involved in bone morphogenesis and remodeling. Genotypes at the LTBP3:c.158delG variant perfectly co-segregated with the phenotype in the investigated family. The available experimental data together with current knowledge on LTBP3 variants and their functional impact in human patients and mice suggest LTBP3:c.158delG as a candidate causative variant for the observed skeletal malformations in British Shorthair cats."

Clinical features: "Two British Shorthair littermates, one male and one female, with deteriorating paraparesis and their unaffected parents were investigated. The litter consisted of two affected and three non-affected kittens. The breeder noticed first signs of hind limb paraparesis in the affected kittens at 8 weeks of age. At 10 weeks of age, a clinical and neurological examination demonstrated lordosis and scoliosis, T3-L3 myelopathy and reduced motility of the intestine. Both kittens showed ambulatory paraparesis. Hematology and cerebrospinal fluid analyses were inconspicuous. Radiography demonstrated severe vertebral column deformations and marked coprostasis. Due to the severity of the clinical signs, the kittens were euthanized." (Rudd Garces et al., 2021).

Pathology: "The post mortem examination of the male affected kitten by CT and MRI confirmed the deformation of multiple thoracic vertebral bodies. From T11 to L3, there was moderate to marked stenosis of the vertebral canal (lateral narrowing) as well as secondary compression of the spinal cord tissue, which could have led to the T3-L3 myelopathy. The MRI images also revealed an ascending and descending dilation of the central canal of the spinal cord (hydromyelia) and cerebellar herniation. At necropsy, the multiple skeletal malformations with shortened legs, deviations of the spine and flattening of the occiput with narrowing of the caudal cranial fossa were corroborated. Parts of the caudal cerebellum and vermis were irreversibly dislocated into the foramen magnum with prominent indented deformation. The thoracic vertebral column showed a mild dorsal bend (kyphosis) with a following, moderate, ventral deformation (lordosis) and a minor lateral deviation (scoliosis) accompanied by a focal stenosis of the spinal canal at T11–12. The ventral cortical laminar bone showed an increased density and thickening up to 1 mm and the woven bone of the vertebral body was irregularly arranged. The ventral cortical laminar bone of the vertebral bodies showed an increased density and thickening up to 1 mm and the woven bone of the vertebral body and femur was irregularly arranged. Except for the compression of the caudal cerebellum, the histopathological examination of the brain was unremarkable. The compression of the thoracic spinal cord was associated with myelin damage accentuated in the dorso-lateral funiculi but also seen in the ventral aspects with dilation of myelin sheaths, axonal swelling (spheroid formation) and degeneration. The coprostasis was caused by annular constrictions of the colon and rectum with distention of anterior aspects. The constricted areas of the intestine showed a marked hypertrophy of the muscle layer with loss of neurons in the submucosal (Meissner) and myenteric (Auerbach) plexus (hypoganglionosis). The thickening of the intestinal wall was accompanied by proliferation of vascularized fibrous connective tissue (granulation tissue) in the submucosa, between the muscle layers as well as the subserosa. Despite the loss of neurons, there was an excessive proliferation of nerve fibers interwoven into the granulation tissue and crossing the muscular layers." (Rudd Garces et al., 2021).

Breed: British Shorthair (Cat) (VBO_0100052).
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: