Asadollahi, Reza, Strauss, Justin E., Zenker, Martin, Beuing, Oliver ORCID: 0000-0001-8033-063X, Edvardson, Simon, Elpeleg, Orly, Strom, Tim M., Joset, Pascal, Niedrist, Dunja, Otte, Christine, Oneda, Beatrice, Boonsawat, Paranchai, Azzarello-Burri, Silvia, Bartholdi, Deborah, Papik, Michael, Zweier, Markus, Haas, Cordula ORCID: 0000-0001-8122-1427, Ekici, Arif B., Baumer, Alessandra, Boltshauser, Eugen, Steindl, Katharina, Nothnagel, Michael ORCID: 0000-0001-8305-7114, Schinzel, Albert, Stoeckli, Esther T. and Rauch, Anita ORCID: 0000-0003-2930-3163 (2018). Clinical and experimental evidence suggest a link between KIF7 and C5orf42-related ciliopathies through Sonic Hedgehog signaling. Eur. J. Hum. Genet., 26 (2). S. 197 - 210. LONDON: NATURE PUBLISHING GROUP. ISSN 1476-5438

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Abstract

Acrocallosal syndrome (ACLS) is an autosomal recessive neurodevelopmental disorder caused by KIF7 defects and belongs to the heterogeneous group of ciliopathies related to Joubert syndrome (JBTS). While ACLS is characterized by macrocephaly, prominent forehead, depressed nasal bridge, and hypertelorism, facial dysmorphism has not been emphasized in JBTS cohorts with molecular diagnosis. To evaluate the specificity and etiology of ACLS craniofacial features, we performed whole exome or targeted Sanger sequencing in patients with the aforementioned overlapping craniofacial appearance but variable additional ciliopathy features followed by functional studies. We found (likely) pathogenic variants of KIF7 in 5 out of 9 families, including the original ACLS patients, and delineated 1000 to 4000-year-old Swiss founder alleles. Three of the remaining families had (likely) pathogenic variants in the JBTS gene C5orf42, and one patient had a novel de novo frameshift variant in SHH known to cause autosomal dominant holoprosencephaly. In accordance with the patients' craniofacial anomalies, we showed facial midline widening after silencing of C5orf42 in chicken embryos. We further supported the link between KIF7, SHH, and C5orf42 by demonstrating abnormal primary cilia and diminished response to a SHH agonist in fibroblasts of C5orf42-mutated patients, as well as axonal pathfinding errors in C5orf42-silenced chicken embryos similar to those observed after perturbation of Shh signaling. Our findings, therefore, suggest that beside the neurodevelopmental features, macrocephaly and facial widening are likely more general signs of disturbed SHH signaling. Nevertheless, long-term follow-up revealed that C5orf42-mutated patients showed catch-up development and fainting of facial features contrary to KIF7-mutated patients.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Asadollahi, RezaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Strauss, Justin E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zenker, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beuing, OliverUNSPECIFIEDorcid.org/0000-0001-8033-063XUNSPECIFIED
Edvardson, SimonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Elpeleg, OrlyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Strom, Tim M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Joset, PascalUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Niedrist, DunjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Otte, ChristineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Oneda, BeatriceUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boonsawat, ParanchaiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Azzarello-Burri, SilviaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bartholdi, DeborahUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Papik, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zweier, MarkusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Haas, CordulaUNSPECIFIEDorcid.org/0000-0001-8122-1427UNSPECIFIED
Ekici, Arif B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baumer, AlessandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boltshauser, EugenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Steindl, KatharinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nothnagel, MichaelUNSPECIFIEDorcid.org/0000-0001-8305-7114UNSPECIFIED
Schinzel, AlbertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stoeckli, Esther T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rauch, AnitaUNSPECIFIEDorcid.org/0000-0003-2930-3163UNSPECIFIED
URN: urn:nbn:de:hbz:38-197441
DOI: 10.1038/s41431-017-0019-9
Journal or Publication Title: Eur. J. Hum. Genet.
Volume: 26
Number: 2
Page Range: S. 197 - 210
Date: 2018
Publisher: NATURE PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 1476-5438
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
GENOTYPE-PHENOTYPE CORRELATIONS; SEVERE MENTAL-RETARDATION; JOUBERT-SYNDROME; ACROCALLOSAL SYNDROME; HALLUX DUPLICATION; COMMISSURAL AXONS; CORPUS-CALLOSUM; MUTATIONS; FEATURES; DISORDERSMultiple languages
Biochemistry & Molecular Biology; Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/19744

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