Universität zu Köln

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:	Creators Email ORCID ORCID Put Code Asadollahi, Reza UNSPECIFIED UNSPECIFIED UNSPECIFIED Strauss, Justin E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Zenker, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Beuing, Oliver UNSPECIFIED orcid.org/0000-0001-8033-063X UNSPECIFIED Edvardson, Simon UNSPECIFIED UNSPECIFIED UNSPECIFIED Elpeleg, Orly UNSPECIFIED UNSPECIFIED UNSPECIFIED Strom, Tim M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Joset, Pascal UNSPECIFIED UNSPECIFIED UNSPECIFIED Niedrist, Dunja UNSPECIFIED UNSPECIFIED UNSPECIFIED Otte, Christine UNSPECIFIED UNSPECIFIED UNSPECIFIED Oneda, Beatrice UNSPECIFIED UNSPECIFIED UNSPECIFIED Boonsawat, Paranchai UNSPECIFIED UNSPECIFIED UNSPECIFIED Azzarello-Burri, Silvia UNSPECIFIED UNSPECIFIED UNSPECIFIED Bartholdi, Deborah UNSPECIFIED UNSPECIFIED UNSPECIFIED Papik, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Zweier, Markus UNSPECIFIED UNSPECIFIED UNSPECIFIED Haas, Cordula UNSPECIFIED orcid.org/0000-0001-8122-1427 UNSPECIFIED Ekici, Arif B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Baumer, Alessandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Boltshauser, Eugen UNSPECIFIED UNSPECIFIED UNSPECIFIED Steindl, Katharina UNSPECIFIED UNSPECIFIED UNSPECIFIED Nothnagel, Michael UNSPECIFIED orcid.org/0000-0001-8305-7114 UNSPECIFIED Schinzel, Albert UNSPECIFIED UNSPECIFIED UNSPECIFIED Stoeckli, Esther T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Rauch, Anita UNSPECIFIED orcid.org/0000-0003-2930-3163 UNSPECIFIED
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:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language GENOTYPE-PHENOTYPE CORRELATIONS; SEVERE MENTAL-RETARDATION; JOUBERT-SYNDROME; ACROCALLOSAL SYNDROME; HALLUX DUPLICATION; COMMISSURAL AXONS; CORPUS-CALLOSUM; MUTATIONS; FEATURES; DISORDERS Multiple languages Biochemistry & Molecular Biology; Genetics & Heredity Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/19744