Male germ cells and photoreceptors, both dependent on close cell–cell interactions, degenerate upon ClC-2 Cl− channel disruption

Abstract

The functions of some CLC Cl(-) channels are evident from human diseases that result from their mutations, but the role of the broadly expressed ClC-2 Cl(-) channel is less clear. Several important functions have been attributed to ClC-2, but contrary to these expectations ClC-2-deficient mice lacked overt abnormalities except for a severe degeneration of the retina and the testes, which led to selective male infertility. Seminiferous tubules did not develop lumina and germ cells failed to complete meiosis. Beginning around puberty there was a massive death of primary spermatocytes and later also of spermatogonia. Tubules were filled with abnormal Sertoli cells, which normally express ClC-2 in patches adjacent to germ cells. In the retina, photoreceptors lacked normal outer segments and degenerated between days P10 and P30. The current across the retinal pigment epithelium was severely reduced at P36. Thus, ClC-2 disruption entails the death of two cell types which depend on supporting cells that form the blood-testes and blood-retina barriers. We propose that ClC-2 is crucial for controlling the ionic environment of these cells.

3q26.33–3q27.2 microdeletion: A new microdeletion syndrome?

“…Gain of function mutations in this gene have been shown to be responsible for hereditary thrombocythaemia [8,9]. CLCN2, a gene for which the mice knock-out model of its homolog demonstrates leukoencephalopathy [10] and degeneration of retinal and testicular cells, leading to male infertility is present in the deleted region [11]. The CLCN2 rat homolog is expressed in fetal lung and its expression rapidly decreases after birth; therefore its deficiency may be related to the neonatal respiratory distress [12] and testicular anomalies observed in our patients.…”

Molecular Targets for Antiepileptic Drug Development

“…ClC-2 knockout mice do not have epilepsy. 172 In humans, however, ClC-2 mutations cosegregated in three families with various idiopathic generalized epilepsy syndromes, including JME, juvenile absence epilepsy, CAE, and epilepsy with grand mal seizures on awakening (EGMA). 173 Functional studies in transfected cells suggest that the mutations cause a loss of function.…”

Additional Disruption of the ClC-2 Cl- Channel Does Not Exacerbate the Cystic Fibrosis Phenotype of Cystic Fibrosis Transmembrane Conductance Regulator Mouse Models

“…Many physiological functions have been postulated for ClC-2 (9), but blindness and male infertility were, surprisingly, the only phenotypes noted in ClC-2 knock-out mouse models (24,25). An impaired transepithelial transport across the retinal pigment epithelium and Sertoli cells was hypothesized as the mechanism underlying the retinal and testicular degeneration, respectively (24). Indeed, Ussing chamber experiments revealed that transepithelial voltage and resistance were reduced in the pigment epithelium of Clcn2 Ϫ/Ϫ mice (24).…”

“…An impaired transepithelial transport across the retinal pigment epithelium and Sertoli cells was hypothesized as the mechanism underlying the retinal and testicular degeneration, respectively (24). Indeed, Ussing chamber experiments revealed that transepithelial voltage and resistance were reduced in the pigment epithelium of Clcn2 Ϫ/Ϫ mice (24).…”