Normal vision and development in mice with low functional expression of Kir7.1 in heterozygosis for a blindness-producing mutation inactivating the channel: NA

Título traducido de la contribución: Desarrollo y visión normales en ratones con baja expresión funcional de Kir7.1 en heterocigotos para una mutación conducente a la ceguera que inactiva el canal

Isabel Margarita Cornejo Araneda, Francisco Leandro Sepúlveda Valenzuela*, Luis Pablo Cid Soto*, Erwin Vera, Juan Carlos Henao, Felipe Tribiños, Johanna Burgos

*Autor correspondiente de este trabajo

Producción científica: Contribución a una revistaArtículorevisión exhaustiva

2 Citas (Scopus)

Resumen

Kþ channel Kir7.1 expressed at the apical membrane of the retinal pigment epithelium (RPE) plays an essential role in retinal function. An isoleucine-to-threonine mutation at position 120 of the protein is responsible for blindness-causing vitreo-retinal dystrophy. We have studied the molecular mechanism of action of Kir7.1-I120T in vitro by heterologous expression and in vivo in
CRISPR-generated knockin mice. Full-size Kir7.1-I120T reaches the plasma membrane but lacks any activity. Analysis of Kir7.1 and the I120T mutant in mixed transfection experiments, and that of tandem tetrameric constructs made by combining wild type (WT) and mutant protomers, leads us to conclude that they do not form heterotetramers in vitro. Homozygous I120T/I120T mice show cleft palate and tracheomalacia and do not survive beyond P0, whereas heterozygous WT/I120T develop normally. Membrane conductance of RPE cells isolated from WT/WT and heterozygous WT/I120T mice is dominated by Kir7.1 current. Using Rbþ as a
charge carrier, we demonstrate that the Kir7.1 current of WT/I120T RPE cells corresponds to approximately 50% of that in cells from WT/WT animals, in direct proportion to WT gene dosage. This suggests a lack of compensatory effects or interference from the mutated allele product, an interpretation consistent with results obtained using WT/– hemizygous mouse. Electroretinography and behavioral tests also show normal vision in WT/I120T animals. The hypomorphic ion channel phenotype of heterozygous Kir7.1-I120T mutants is therefore compatible with normal development and retinal function. The lack of detrimental effect of this degree of functional deficit might explain the recessive nature of Kir7.1 mutations causing human eye disease.
Título traducido de la contribuciónDesarrollo y visión normales en ratones con baja expresión funcional de Kir7.1 en heterocigotos para una mutación conducente a la ceguera que inactiva el canal
Idioma originalInglés
Páginas (desde-hasta)C1178-C1192
PublicaciónAmerican Journal of Physiology - Cell Physiology
Volumen326
N.º4
DOI
EstadoPublicada - 2024

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© 2024 American Physiological Society. All rights reserved.

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