TY - JOUR T1 - Mutations in <em>MYO1H</em> cause a recessive form of central hypoventilation with autonomic dysfunction JF - Journal of Medical Genetics JO - J Med Genet DO - 10.1136/jmedgenet-2017-104765 SP - jmedgenet-2017-104765 AU - Malte Spielmann AU - Luis R Hernandez-Miranda AU - Isabella Ceccherini AU - Debra E Weese-Mayer AU - Bjørt K Kragesteen AU - Izabela Harabula AU - Peter Krawitz AU - Carmen Birchmeier AU - Norma Leonard AU - Stefan Mundlos Y1 - 2017/08/04 UR - http://jmg.bmj.com/content/early/2017/08/04/jmedgenet-2017-104765.abstract N2 - Background 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 PHOX2B. The objective of the present study was to identify the molecular cause of a recessive form of central hypoventilation with autonomic dysfunction.Methods 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.Results We report on a consanguineous family with three affected children, all tested PHOX2B mutation negative, presenting with alveolar hypoventilation and symptoms of autonomic dysregulation. Whole-genome sequencing revealed a homozygous frameshift mutation in exon 25 of the MYO1H gene (c.2524_2524delA) segregating with the phenotype in the family. MYO1H encodes for the unconventional myosin IH, which is thought to function as a motor protein in intracellular transport and vesicle trafficking. We show that Myo1h 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 Myo1h mutant mouse strains: the first strain (Myo1h*) resembling the human mutation and the second being a full knock-out (Myo1hFS). Whole-body plethysmography studies in Myo1h* newborns with the re-engineered human mutation revealed hypoventilation and a blunted response to CO2, recapitulating the breathing phenotype observed in the kindred.Conclusions Our results identify MYO1H as an important gene in CO2 sensitivity and respiratory control and as the cause of a rare recessive form of congenital central hypoventilation. ER -