Heterozygous truncating variants in SUFU cause congenital ocular motor apraxia.
COMA
Joubert syndrome
SUFU
congenital ocular motor apraxia
sonic hedgehog
Journal
Genetics in medicine : official journal of the American College of Medical Genetics
ISSN: 1530-0366
Titre abrégé: Genet Med
Pays: United States
ID NLM: 9815831
Informations de publication
Date de publication:
02 2021
02 2021
Historique:
received:
24
06
2020
accepted:
17
09
2020
revised:
11
09
2020
pubmed:
8
10
2020
medline:
4
6
2021
entrez:
7
10
2020
Statut:
ppublish
Résumé
This study aimed to delineate the genetic basis of congenital ocular motor apraxia (COMA) in patients not otherwise classifiable. We compiled clinical and neuroimaging data of individuals from six unrelated families with distinct clinical features of COMA who do not share common diagnostic characteristics of Joubert syndrome or other known genetic conditions associated with COMA. We used exome sequencing to identify pathogenic variants and functional studies in patient-derived fibroblasts. In 15 individuals, we detected familial as well as de novo heterozygous truncating causative variants in the Suppressor of Fused (SUFU) gene, a negative regulator of the Hedgehog (HH) signaling pathway. Functional studies showed no differences in cilia occurrence, morphology, or localization of ciliary proteins, such as smoothened. However, analysis of expression of HH signaling target genes detected a significant increase in the general signaling activity in COMA patient-derived fibroblasts compared with control cells. We observed higher basal HH signaling activity resulting in increased basal expression levels of GLI1, GLI2, GLI3, and Patched1. Neuroimaging revealed subtle cerebellar changes, but no full-blown molar tooth sign. Taken together, our data imply that the clinical phenotype associated with heterozygous truncating germline variants in SUFU is a forme fruste of Joubert syndrome.
Identifiants
pubmed: 33024317
doi: 10.1038/s41436-020-00979-w
pii: S1098-3600(21)02539-9
pmc: PMC7862056
doi:
Substances chimiques
Hedgehog Proteins
0
Kruppel-Like Transcription Factors
0
Repressor Proteins
0
SUFU protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
341-351Références
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