Mutations in <i>MYO1H</i> cause a recessive form of central hypoventilation with autonomic dysfunction.

Abstract

Congenital central hypoventilation syndrome (CCHS) is a rare life-threatening disorder of respiratory and autonomic regulation. It is classically caused by dominant mutations in the transcription factor <i>PHOX2B</i>. The objective of the present study was to identify the molecular cause of a recessive form of central hypoventilation with autonomic dysfunction. Here, we used homozygosity mapping and whole-genome sequencing in a consanguineous family with CCHS in combination with functional analyses in CRISPR/Cas9 engineered mice. We report on a consanguineous family with three affected children, all tested <i>PHOX2B</i> mutation negative, presenting with alveolar hypoventilation and symptoms of autonomic dysregulation. Whole-genome sequencing revealed a homozygous frameshift mutation in exon 25 of the <i>MYO1H</i> gene (c.2524_2524delA) segregating with the phenotype in the family. <i>MYO1H</i> encodes for the unconventional myosin IH, which is thought to function as a motor protein in intracellular transport and vesicle trafficking. We show that <i>Myo1h</i> is broadly expressed in the mouse lower medulla, including the CO₂-sensitive Phox2b+ retrotrapezoid neurons. To test the pathogenicity of the variant, we engineered two <i>Myo1h</i> mutant mouse strains: the first strain (<i>Myo1h*</i>) resembling the human mutation and the second being a full knock-out (<i>Myo1h^FS</i> ). Whole-body plethysmography studies in <i>Myo1h*</i> newborns with the re-engineered human mutation revealed hypoventilation and a blunted response to CO₂, recapitulating the breathing phenotype observed in the kindred. Our results identify <i>MYO1H</i> as an important gene in CO₂ sensitivity and respiratory control and as the cause of a rare recessive form of congenital central hypoventilation.