Schroeder, Simone, Li, Yun, Yigit, Gokhan, Altmueller, Janine, Bader, Ingrid, Bevot, Andrea, Biskup, Saskia, Dreha-Kulaczewski, Steffi, Korenke, G. Christoph, Kottke, Raimund, Mayr, Johannes A., Preisel, Martin, Toelle, Sandra P., Wente-Schulz, Sarah, Wortmann, Saskia B., Hahn, Heidi, Boltshauser, Eugen, Uhmann, Anja, Wollnik, Bernd and Brockmann, Knut . Heterozygous truncating variants inSUFUcause congenital ocular motor apraxia. Genet. Med.. LONDON: SPRINGERNATURE. ISSN 1530-0366

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Abstract

Purpose This study aimed to delineate the genetic basis of congenital ocular motor apraxia (COMA) in patients not otherwise classifiable. Methods 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. Results 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 ofGLI1,GLI2,GLI3, andPatched1. Neuroimaging revealed subtle cerebellar changes, but no full-blown molar tooth sign. Conclusion Taken together, our data imply that the clinical phenotype associated with heterozygous truncating germline variants inSUFUis aforme frusteof Joubert syndrome.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Schroeder, SimoneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Li, YunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yigit, GokhanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bader, IngridUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bevot, AndreaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Biskup, SaskiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dreha-Kulaczewski, SteffiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Korenke, G. ChristophUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kottke, RaimundUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mayr, Johannes A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Preisel, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Toelle, Sandra P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wente-Schulz, SarahUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wortmann, Saskia B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hahn, HeidiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boltshauser, EugenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Uhmann, AnjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wollnik, BerndUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brockmann, KnutUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-315580
DOI: 10.1038/s41436-020-00979-w
Journal or Publication Title: Genet. Med.
Publisher: SPRINGERNATURE
Place of Publication: LONDON
ISSN: 1530-0366
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
JOUBERT SYNDROME; MUTATIONS; GENEMultiple languages
Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/31558

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