Attractin (ATRN) deficiencies cause darkened pigmentation, increased locomotor activity, decreased body weight, and vacuolization and myelination defects in the central nervous system.

Agouti protein competes with alpha-melanocyte stimulating hormone (a-MSH) for binding of melanocortin 1 receptor (MC1R), and this in turn signals pigment type switching from eumelanin production to pheomelanin production. ATRN interacts with agouti possibly to facilitate the interaction with MC1R. In mice, ATRN deficiencies result in decreased pheomelanin production causing darkened ears, tail, feet, and coat color which becomes dark reddish brown as these mice age. Thus, the initial Atrn mutation reported by Lane and Green was called mahogany (Atrn^mg). ATRN deficiencies darken the coloring caused by nonagouti such that these mice are coal black with no white hairs behind the ears or around the perineum and have blacker ears, tail, and feet. ATRN deficiency can suppress the impact on coat color of the A^y allele but not the Mc1r^e allele. The Atrn^mg allele is hypomorphic while the Atrn^mg-3J allele results from a deletion that is thought to yield a null mutation. While both alleles cause darkened coat color due to decreased pheomelanin production, the increased severity of the Atrn^mg-3J allele is evident in the coat color of mahogany mice carrying the yellow allele of agouti: A^y Atrn^mg/A Atrn^mg mice are dark brown on the back but yellow on the belly while A^y Atrn^mg-3J/A Atrn^mg-3J mice are entirely black with dark ears and tail. (He et al., 2001.)

In the central nervous system, alpha melanocortin hormone (a-MSH) interacts with MC4R, and agouti related protein competes with a-MSH for binding to MC4R. These interactions are important for the regulation of body weight. Agouti protein, which is normally expressed only in the skin, can compete with a-MSH for binding to MC4R. Thus, mice carrying the A^y allele which causes systemic expression of Agouti protein are hyperphagic and develop hyperinsulinemia, hyperleptinemia, hyperglycemia, increased linear growth, and obesity. Atrn^mg and Atrn^mg-3J have each been shown to suppress some or all of these A^y induced characteristics. While the mahogany mutations are generally characterized as recessive, Miller et al. reported that Atrn^mg can suppress in a semidominant manner both the coat color and obesity induced by A^y. Dinulescu et al. reported that mice homozygous for Atrn^mg on a C57BL/6J congenic background have increased nighttime locomotor activity, a 0.5 degree increase in body temperature, and increased basal metabolic rate, and are hyperphagic. Gunn et al. reported that mice homozygous for Atrn^mg-3J on the C3H/HeJ background and mice homozygous for Atrn^mg on a C3H/HeJ congenic background also have increased nighttime locomotor activity but that they have normal food intake and decreased body weight associated with decreased adiposity. Mice homozygous for Atrn^mg-3J have decreased fat storage and are resistant to weight gain when fed a high fat diet. Atrn mutations do not alter the obesity caused by a null mutation of Mcr4 or transgenic expression of Agouti related protein, nor do they inhibit obesity caused by the tub, Cpe^fat, Lepr^ob or Lepr^db alleles. (Nagle et al., 1999; He et al., 2001; Dinulescu et al., 1998.)

In addition to their coat color changes and metabolic changes, Atrn deficient mice also have been found to have vacuolization in brain tissue. He et al. reported finding 5-40uM vacuoles in both the gray and white matter of mice homozygous for the Atrn^mg-3J allele on a segregating background of C3H/HeJ and C57BL/6J. These were found in the brainstem, cerebellar medulla, granular layer of the cerebellum, pons, thalamus, hippocampus, caudate and putamen, somatosensory cortex and spinal cord gray matter, and fewer were found in the primary motor cortex, visual cortex, and white matter tracts of the spinal cord. Transgenic expression of attractin driven by the Beta-actin promoter prevented this phenotype in mice homozygous for Atrn^mg-3J but did not cause any additional obvious phenotype. Kuramoto et al. found vacuoles up to 10-20uM in diameter widely distributed in the brainstem, cerebral cortex, cerebellum, and spinal cord of 40 day old mice homozygous for the Atrn^mg-3J allele on the C3H/HeJ background. They also described aberrant myelination and a mild tremor (17 Hz) in the adults. Bronson et al. found vacuoles in brain samples of mice homozygous for the Atrn^mg, Atrn^mg-3J, and Atrn^6J alleles as well as Atrn^mg/Atrn^mg-6J and Atrn^mg-3J/Atrn^mg-6J heterozygotes. The severity of this phenotype increased with age and varied between strains. By two months of age, vacuoles were found in the granule layer of the cerebellar cortex, deeper layers of the cerebral cortex, and various nuclei of the medulla, midbrain, and thalamus, and by nine months of age vacuoles were found throughout the brain. These vacuoles were generally not found in white matter tracts. Electron microscopy showed vacuoles in the axons, dendrites, and neuronal soma. Myelination defects specific to the central nervous system were found in mice homozygous for the mg-6J allele of Atrn but not other mutant alleles of Atrn. Bronson et al. also described severe tremors and a sprawling gait in Atrn^mg-6J/Atrn^mg-6J mice on the CAST/Ei background and decreased severity after backcrossing to C3H/SnJ. They also found that Atrn^mg-3J/Atrn^mg-3J mice are prone to "seizures that begin with a sudden freezing of motion and progress to tonic-clonic movements". They did not find seizures in Atrn^mg/Atrn^mgmice. In the rat, the zitter allele of attractin has been found to cause hypomyelination and vacuolization in the central nervous system resulting in early-onset tremor. (Kuramoto et al., 2001.)