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Mutations in MYO1H cause a recessive form of central hypoventilation with autonomic dysfunction
  1. Malte Spielmann1,2,
  2. Luis R Hernandez-Miranda3,
  3. Isabella Ceccherini4,
  4. Debra E Weese-Mayer5,6,
  5. Bjørt K Kragesteen1,
  6. Izabela Harabula1,
  7. Peter Krawitz2,
  8. Carmen Birchmeier3,
  9. Norma Leonard7,
  10. Stefan Mundlos1,2
  1. 1 Max-Planck-Institute for Molecular Genetics, Berlin, Germany
  2. 2 Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin, Berlin, Germany
  3. 3 Max-Delbrück-Centrum für Molekulare Medizin in der Helmholtz-Gemeinschaft, Germany
  4. 4 UOC Genetica Medica, Istituto G Gaslini, Genova, Italy
  5. 5 Center for Autonomic Medicine in Pediatrics (CAMP), Ann & Robert H. Lurie Children’s Hospital of Chicago, Stanley Manne Children’s Research Institute, Chicago, Illinois, USA
  6. 6 Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
  7. 7 Department of Medical Genetics, University of Alberta, Edmonton, Canada
  1. Correspondence to Stefan Mundlos, Max-Planck-Institute for Molecular Genetics, Ihnestraße 63-73, 14195 Berlin, Germany ; mundlos{at}


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.

  • Congenital central hypoventilation syndrome (CCHS)
  • Ondine’s curse
  • MYO1H
  • CRISPR/Cas9

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  • Contributors Patient recruitment and phenotyping: MS, IC, DEW-M, NL and SM; CRISPR experiments and mouse phenotyping: MS, LRH-M, BKK, IH and CB and SM; bioinformatics analyses: PK. All authors contributed in writing and reviewing the manuscript.

  • Funding This project was supported by grants from the Deutsche Forschungsgemeinschaft (DFG) to SM and CB. MS was supported by a grant from the DFG (SP1532/2-1) and by a fellowship of the Berlin-Brandenburg School for Regenerative Therapies, Berlin, Germany. LRH-M was supported by a grant from the European Commission under the scheme of Marie Skłodowska-Curie Intra-European fellowship (302477).

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval The study was performed with the approval of the Charité Ethics Committee, Berlin, Germany.

  • Provenance and peer review Not commissioned; externally peer reviewed.