Gene Regulatory Patterns for Cdh6 Expression Identify Divisible Genetic Compartments in the Postnatal Mouse Cerebral Cortex

Fabry disease (OMIM 301500) is a rare X-linked recessive disorder caused by mutations in the α-galactosidase gene (Gla). Loss of Gla activity leads to the abnormal accumulation of glycosphingolipids in lysosomes of predominantly vascular endothelial cells. Clinically the disorder presents with angiokeratomas, clouding of the cornea, and renal, cardiac, and cerebrovascular complications. In addition, there is an increased incidence of sensorineural hearing loss in Fabry patients. In this study, we investigated the loss of α-galactosidase A activity on hearing function in Gla-deficient mice (Glatm1Kul). Gla mRNA was readily detected in the cochlea of 2- and 12-month old C57BL/6J and C3HeB/FeJ mice. The targeted allele was introgressed to the normal hearing C3HeB/FeJ strain to eliminate confounding genetic background effects. Auditory brain stem responses (ABR) to click, 8-, 16-, and 32 kHz stimuli measured at regular intervals from animals at the N4 backcross generation and from N4F1 hybrids demonstrated normal hearing in hemizygous and homozygous mutant mice up to 76 weeks of age. By histological criteria, the cyto-architecture of the mutant cochlea showed a normal appearance. The data demonstrate that in the mouse the loss of α-galactosidase A activity is genetically or biochemically buffered and not sufficient per se to cause an appreciable degree of hearing impairment.