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Rare hypomorphic human variation in the heptahelical domain of SMOOTHENED contributes to holoprosencephaly phenotypes
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  • Momoko Nagai-Tanima,
  • Sungkook Hong,
  • Ping Hu,
  • Blake Carrington,
  • Raman Sood,
  • Erich Roessler,
  • Maximilian Muenke
Momoko Nagai-Tanima
Kyoto University
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Sungkook Hong
National Institutes of Health
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Ping Hu
National Institutes of Health
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Blake Carrington
National Institutes of Health
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Raman Sood
National Institutes of Health
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Erich Roessler
NHGRI
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Maximilian Muenke
NHGRI/NIH
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Abstract

Holoprosencephaly (HPE) is the most common congenital anomaly affecting the forebrain and face in humans and occurs as frequently as 1:250 conceptions or 1:10,000 livebirths. Sonic hedgehog (SHH) is one of the best characterized HPE genes that plays crucial roles in numerous developmental processes including midline neural patterning and craniofacial development. The Frizzled class G-Protein Coupled Receptor (GPCR) SMOOTHENED (SMO), whose signalling activity is tightly regulated, is the sole obligate transducer of hedgehog-related signals. However, except for previous reports of somatic oncogenic driver mutations in human cancers (or mosaic tumors in rare syndromes), any potential disease-related role of SMO genetic variation in humans is largely unknown. To our knowledge, ours is the first report of a human hypomorphic variant revealed by functional testing of seven distinct non-synonymous SMO variants derived from HPE molecular and clinical data. Here we describe several zebrafish bioassays developed and guided by a systems biology analysis. This analysis strategy, and detection of hypomorphic variation in human SMO, demonstrates the necessity of integrating the genomic variant findings in HPE probands with other components of the hedgehog gene regulatory network (GRN) in overall medical interpretations.

Peer review status:ACCEPTED

30 Mar 2020Submitted to Human Mutation
04 Apr 2020Submission Checks Completed
04 Apr 2020Assigned to Editor
13 Apr 2020Reviewer(s) Assigned
29 Apr 2020Review(s) Completed, Editorial Evaluation Pending
14 May 2020Editorial Decision: Revise Major
17 Jul 20201st Revision Received
17 Jul 2020Assigned to Editor
17 Jul 2020Submission Checks Completed
17 Jul 2020Reviewer(s) Assigned
27 Jul 2020Review(s) Completed, Editorial Evaluation Pending
08 Aug 2020Editorial Decision: Revise Minor
14 Aug 20202nd Revision Received
14 Aug 2020Assigned to Editor
14 Aug 2020Submission Checks Completed
14 Aug 2020Review(s) Completed, Editorial Evaluation Pending
28 Aug 2020Editorial Decision: Accept