Clinical and experimental evidence suggest a link between KIF7 and C5orf42-related ciliopathies through Sonic Hedgehog signaling

Asadollahi R, Strauss JE, Zenker M, Beuing O, Edvardson S, Elpeleg O, Strom TM, Joset P, Niedrist D, Otte C, Oneda B, Boonsawat P, Azzarello-Burri S, Bartholdi D, Papik M, Zweier M, Haas C, Ekici AB, Baumer A, Boltshauser E, Steindl K, Nothnagel M, Schinzel A, Stoeckli ET, Rauch A (2018)

Publication Type: Journal article

Publication year: 2018

Journal

European Journal of Human Genetics Nature Publishing Group: Open Access Hybrid Model Option B

Book Volume: 26

Pages Range: 197-209

Journal Issue: 2

DOI: 10.1038/s41431-017-0019-9

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.

Authors with CRIS profile

Arif Bülent Ekici Institute of Human Genetics

Involved external institutions

Otto-von-Guericke-Universität Magdeburg DE Germany (DE) University of Zurich / Universität Zürich (UZH) CH Switzerland (CH) Universitätsklinikum Magdeburg A.ö.R. DE Germany (DE) Universität zu Köln DE Germany (DE) Universitäts-Kinderspital Zürich CH Switzerland (CH) Hadassah Medical Center / מרכז רפואי הדסה‎‎ IL Israel (IL) Technische Universität München (TUM) DE Germany (DE)

How to cite

APA:

Asadollahi, R., Strauss, J.E., Zenker, M., Beuing, O., Edvardson, S., Elpeleg, O.,... Rauch, A. (2018). Clinical and experimental evidence suggest a link between KIF7 and C5orf42-related ciliopathies through Sonic Hedgehog signaling. European Journal of Human Genetics, 26(2), 197-209. https://doi.org/10.1038/s41431-017-0019-9

MLA:

Asadollahi, Reza, et al. "Clinical and experimental evidence suggest a link between KIF7 and C5orf42-related ciliopathies through Sonic Hedgehog signaling." European Journal of Human Genetics 26.2 (2018): 197-209.

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