KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes
Authors: Christel Thauvin-Robinet
Stanislas Lyonnet
Raoul Hennekam
Koray Boduroglu
Nicolas Goudin
Férechté Encha-Razavi
Nicholas Katsanis
Alain Schmitt
Mark Winey
Philip L Beales
Laura Fertitta
Jean-Pierre Siffroi
Marie Gonzales
Tania Attié-Bitach
Nicole Joyé
Marie-Hélène Saint Frison
Luc Rigonnot
Yasemin Alanay
Céline Gomes
Valérie Cormier-Daire
Karlien L M Coene
Audrey Putoux
Solenn Pruvost
Nurten Ayse Akarsu
Christine Bole-Feysot
Michel Vekemans
Sophie Thomas
Christopher L Bennett
Sophie Patrier
Arnold Munnich
Nicolas Cagnard
Erica E Davis
Nadia Elkhartoufi
Patrick Nitschke
Gönül Ogur
Elif Uz
Daniela Buzas
Estelle Colin
Gulen Eda Utine
Journal: Nature Genetics (2011)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: KIF7; Hedgehog signaling pathway; GLI transcription factor; ciliopathy; hydrolethalus syndrome
Affiliations: INSERM U-781, Hôpital Necker-Enfants Malades, Paris, France.

Abstract:  KIF7, the human ortholog of Drosophila Costal2, is a key component of the Hedgehog signaling pathway. Here we report mutations in KIF7 in individuals with hydrolethalus and acrocallosal syndromes, two multiple malformation disorders with overlapping features that include polydactyly, brain abnormalities and cleft palate. Consistent with a role of KIF7 in Hedgehog signaling, we show deregulation of most GLI transcription factor targets and impaired GLI3 processing in tissues from individuals with KIF7 mutations. KIF7 is also a likely contributor of alleles across the ciliopathy spectrum, as sequencing of a diverse cohort identified several missense mutations detrimental to protein function. In addition, in vivo genetic interaction studies indicated that knockdown of KIF7 could exacerbate the phenotype induced by knockdown of other ciliopathy transcripts. Our data show the role of KIF7 in human primary cilia, especially in the Hedgehog pathway through the regulation of GLI targets, and expand the clinical spectrum of ciliopathies. 

Retracted: No

PubPeer comments:
 Audrey Putoux and colleagues reported KIF7 mutations in patients they described as hydrolethalus or acrocallosal syndromes. I think that their clinico-radiological descriptions are very poor. For example, they present a case of fetus with this neuropathological examination ![file] And the legend of their figure is: ![file] First, I don t think that the authors can be certain of hydrocephalus because of the poor conditions of this examination. In figure a, the temporal horns of the ventricle are surely not dilated. The lateral ventricles are collapsed. Thus, I don t believe that this examination is compatible with hydrocephalus. Perhaps, the authors can show the results of antenatal exams that established the diagnosis of hydrocephalus in this fetus. Furthermore, in b, the authors stated that the interpeduncular fossa is deep. Such a conclusion is curious, since the section does not involve the peduncular fossa! Indeed, the section is caudal to this structure. Their neuroradiological data are also a matter of concern. ![file] Their interpretation is as follows: ![file] What criteria do the author use to consider that these interpeduncular fossa are deep? For me, they are normal. Correlation between clinics and genetics are very interesting. But they need to be based on very good data obtained by multidisciplinary teams that can discuss and present all the aspects. I am sorry to say that I don t find this in this publication. , 
 Haemonchus contortus #1 You are right. Family 1 is the sole example of the so-called hydrolethalus type 2 in the literature. ![file] This consanguinous family from Algeria presented four fetuses (ages: 11 to 15 weeks of gestation). We don t know the results of ultrasound findings during pregnancy. This should be of prime importance. In case of hydrolethalus syndrome (type 1), hydrocephalus is massive both internal and external. Is it the case here? Two cases were described as anencephalic in table 1 ![file] In the text, they are described as exencephalic (a figure of these two fetuses should be provided by the authors). The authors involved in the analysis of these fetuses should answer my questions: ![file] Dr Sophie Patrier (hopital Armand Trousseau, Paris, France) Dr Marie-Helene Saint Frison (hopital Victor Dupouy, Arhenteuil, France) Dr Ferechte Encha-Razavi (hopital Necker-Enfants-Malades, Paris, France) Dr Jean-Pierre Siffroi (hopital Armand Trousseau, Paris, France) ![file] The authors described molar tooth sign in fetus 3. This sign is never observed in case of hydrolethalus syndrome (Paetau et al. J Neuropathol Exp Neurol 2008;47:750-762). I suggest that this family is not the sole case of hydrolethalus syndrome 2 but a case of Joubert syndrome due to mutation of *KIF7*. ,