Rare hypomorphic human variation in the heptahelical domain of SMO contributes to holoprosencephaly phenotypes.
Amino Acid Sequence
Animals
Gain of Function Mutation
/ genetics
Gene Expression Regulation, Developmental
Gene Regulatory Networks
Holoprosencephaly
/ genetics
Humans
Loss of Function Mutation
/ genetics
Models, Biological
Morpholinos
/ pharmacology
Mutagenesis
/ genetics
Mutation
/ genetics
Phenotype
Protein Domains
Smoothened Receptor
/ chemistry
Zebrafish
/ genetics
Zebrafish Proteins
/ genetics
GPCR
Hedgehog signaling
SMO
holoprosencephaly
zebrafish
Journal
Human mutation
ISSN: 1098-1004
Titre abrégé: Hum Mutat
Pays: United States
ID NLM: 9215429
Informations de publication
Date de publication:
12 2020
12 2020
Historique:
received:
04
04
2020
revised:
14
08
2020
accepted:
28
08
2020
pubmed:
10
9
2020
medline:
26
11
2021
entrez:
9
9
2020
Statut:
ppublish
Résumé
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 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 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 nonsynonymous 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 in overall medical interpretations.
Substances chimiques
Morpholinos
0
SMO protein, human
0
Smoothened Receptor
0
Zebrafish Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2105-2118Informations de copyright
© 2020 Wiley Periodicals LLC.
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