Maternal Inheritance of a Recessive RBP4 Defect in Canine Congenital Eye Disease.

Maternally skewed transmission of traits has been associated with genomic imprinting and oocyte-derived mRNA. We report canine congenital eye malformations, caused by an amino acid deletion (K12del) near the N terminus of retinol-binding protein (RBP4). The disease is only expressed when both dam and offspring are deletion homozygotes. RBP carries vitamin A (retinol) from hepatic stores to peripheral tissues, including the placenta and developing eye, where it is required to synthesize retinoic acid. Gestational vitamin A deficiency is a known risk factor for ocular birth defects. The K12del mutation disrupts RBP folding in vivo, decreasing its secretion from hepatocytes to serum. The maternal penetrance effect arises from an impairment in the sequential transfer of retinol across the placenta, via RBP encoded by maternal and fetal genomes. Our results demonstrate a mode of recessive maternal inheritance, with a physiological basis, and they extend previous observations on dominant-negative RBP4 alleles in humans.

Vitamin A deficiency due to bi-allelic mutation of RBP4: There's more to it than meets the eye.

Vitamin A deficiency is the leading cause of preventable blindness in children worldwide and results in a well-recognized ocular phenotype. Herein we describe a patient presenting to the eye clinic with a retinal dystrophy and ocular colobomata. This combination of clinical signs and consanguineous pedigree structure suggested a genetic basis for the disease, a hypothesis that was tested using whole genome sequencing. Bi-allelic mutations in RBP4 were identified (c.248+1G>A), consistent with a diagnosis of inherited vitamin A deficiency. We describe a constellation of signs that appear to be characteristic for this disease, increasing clinical awareness of this rare condition.

Reduced increase in plasma renin activity on water-deprivation in blind hereditary microphthalmic rats.

We compared the plasma renin activity (PRA) before and after 24-h water-deprivation in blind hereditary microphthalmic rats and Donryu rats. In the congenitally blind rats with a morphologically abnormal suprachiasmatic nucleus (SCN), hypovolemia induced significantly less elevation of the PRA and significantly more increase in the hematocrit value than in normal rats. The changes after water-deprivation in the blind rats were quite similar to those reported in rats with SCN lesions. However, the free-running circadian rhythms persisted in these blind rats, whereas those in rats with SCN lesions were completely eliminated. Thus, it is likely that SCN cells are involved in regulation of the PRA, and that if this is the case these cells are different from those containing the circadian pacemaker.

Little or no induction of hyperglycemia by 2-deoxy-D-glucose in hereditary blind microphthalmic rats.

Studies were made on whether hereditary microphthalmic rats (1), which are congenitally blind, showed a hyperglycemic response to intracerebroventricular injection of 2-deoxy-D-glucose (2DG) in their subjective light period. In contrast to previous findings in normal rats in which 2DG injection caused light-cycle dependent hyperglycemia (2) and bilateral lesion of the suprachiasmatic nucleus (SCN) completely abolished this hyperglycemia (3), 2DG injection caused no and only slight hyperglycemia in male and female rats with hereditary microphthalmia, respectively. Gross and histological examinations indicated that these rats had no optic nerve or retinohypothalamic tract and that their SCN had an abnormal structure. Locomotive activity recordings showed that all the blind rats had a free-running circadian activity rhythm. These findings suggest that the projection sites of the retinohypothalamic tract to the SCN are involved in the mechanism of the hyperglycemic response to 2DG, but that neural cells, which may be responsible for the generation of circadian rhythms, are not. We have reported that when adult rats were blinded by orbital enucleation, their hyperglycemic response to 2DG was suppressed temporarily 3-5 weeks after the operation, but that their plasma insulin level was basically higher and increased further after 2DG injection during this period (4). In congenitally blind rats, however, the basal plasma insulin level was not higher and the level did not change after 2DG treatment. This difference is discussed from the view point of the role of the premature SCN in regulation of the plasma insulin concentration.

Pathogenesis of osteopetrosis in the microphthalmic mouse: reduced bone resorption.

Bone resorption, stimulated by injection of parathyroid extract, was measured in vivo in microphthalmic mice as the rate of release of 3H from bone after incorporation of 3H-proline. Bone resorption in these mice, which inherit osteopetrosis, was less than 10% of the in normal litermates. Autoradiography confirmed the reduction in removal of radioactive bone matrix and in bone growth in microphthalmic mice. The ability of these mice to raise the serum calcium concentration in response to PTE was also reduced. These results, that bone resorption is reduced in microphthalmic mice, are discussed in relation to the pathogenesis and cure of the disease.