PUBLICATION
Rare hypomorphic human variation in the heptahelical domain of SMO contributes to holoprosencephaly phenotypes
- Authors
- Nagai-Tanima, M., Hong, S., Hu, P., Carrington, B., Sood, R., Roessler, E., Muenke, M.
- ID
- ZDB-PUB-200910-12
- Date
- 2020
- Source
- Human Mutation 41(12): 2105-2118 (Journal)
- Registered Authors
- Sood, Raman
- Keywords
- SMO, GPCR, hedgehog signaling, holoprosencephaly, zebrafish
- MeSH Terms
-
- Amino Acid Sequence
- Animals
- Gain of Function Mutation/genetics
- Gene Expression Regulation, Developmental
- Gene Regulatory Networks
- Holoprosencephaly/genetics*
- Holoprosencephaly/pathology*
- Humans
- Loss of Function Mutation/genetics
- Models, Biological
- Morpholinos/pharmacology
- Mutagenesis/genetics
- Mutation/genetics*
- Phenotype
- Protein Domains
- Smoothened Receptor/chemistry*
- Smoothened Receptor/genetics*
- Zebrafish/genetics
- Zebrafish Proteins/genetics
- PubMed
- 32906187 Full text @ Hum. Mutat.
Citation
Nagai-Tanima, M., Hong, S., Hu, P., Carrington, B., Sood, R., Roessler, E., Muenke, M. (2020) Rare hypomorphic human variation in the heptahelical domain of SMO contributes to holoprosencephaly phenotypes. Human Mutation. 41(12):2105-2118.
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 signaling molecule (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 signaling 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. This article is protected by copyright. All rights reserved.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping