Glutaryl-CoA dehydrogenase (GCDH, EC 1.3.99.7) deficiency, known as
glutaric acidemia type I, is one of the more common organic acidurias. To
investigate the role of this pathway in different organs we studied the
tissue-specific expression pattern of rat Gcdh.
The open reading frame cDNA of the rat Gcdh gene was cloned from rat
brain mRNA by RT-PCR, allowing the synthesis of digoxigenin-labeled in
situ hybridization (ISH) riboprobes. Gcdh mRNA expression was analyzed
by ISH on cryosections of adult rat brain, kidney, liver, spleen and heart
muscle, as well as on E15 and E18 rat embryos.
Gcdh was found expressed in the whole rat brain, almost exclusively in
neurons. Gcdh was absent from astrocytes but expressed in rare
oligodendrocytes. Strong Gcdh expression was found in liver and spleen,
where expression appears predominant to lymphatic nodules. In kidney, the
highest Gcdh expression is found in the juxtamedullar cortex (but not in
glomerula), and at lower levels in medulla. Heart muscle was negative.
During embryonic development, Gcdh was found well expressed in liver,
intestinal mucosa and skin, as well as at lower levels in CNS.
Further studies are ongoing to provide evidence on the presence of the
entire pathway in CNS in order to understand the mechanisms leading to
neurotoxicity in glutaric aciduria. The high expression of Gcdh in kidney
may explain why certain patients with residual enzyme activity are low
excretors at the urine metabolite level.