Homozygous STIL mutation causes holoprosencephaly and microcephaly in two siblings
Authors: Sophie Rose
Véronique David
Houda Hamdi-Rozé
Marie de Tayrac
Régis Giet
Sylvie Odent
Wilfrid Carré
Charlotte Mouden
Valérie Dupé
Bénédicte Héron-Longe
Christèle Dubourg
Marie-Claude Babron
Linda Akloul
Journal: PLoS ONE (2015)
Discipline: Multidisciplinary
Keywords: Holoprosencephaly; HPE; STIL; mutation; centriole formation
Affiliations: Institut de Génétique et Développement de Rennes, Equipe Génétique des Pathologies Liées au Développement, Faculté de Médecine, Université de Rennes 1, 35043 Rennes, France., Institut de Génétique et Développement de Rennes, Equipe Génétique des Pathologies Liées au Développement, Faculté de Médecine, Université de Rennes 1, 35043 Rennes, France; Plateforme Génomique Santé, Biosit, Université Rennes 1, 35033 Rennes, France., Institut de Génétique et Développement de Rennes, Equipe Génétique des Pathologies Liées au Développement, Faculté de Médecine, Université de Rennes 1, 35043 Rennes, France; Laboratoire de Génétique Moléculaire et Génomique, CHU Pontchaillou, 35033 Rennes, France., Laboratoire de Génétique Moléculaire et Génomique, CHU Pontchaillou, 35033 Rennes, France., Inserm U946, Variabilité Génétique et Maladies Humaines, Université Paris-Diderot, 75010 Paris, France., Service de Génétique Clinique, Hôpital Sud, 35200 Rennes, France., Service de Pédiatrie, Hôpital Jean Verdier, APHP, 93140 Bondy, France., Institut de Génétique et Développement de Rennes, Equipe Génétique des Pathologies Liées au Développement, Faculté de Médecine, Université de Rennes 1, 35043 Rennes, France; Service de Génétique Clinique, Hôpital Sud, 35200 Rennes, France., Institut de Génétique et Développement de Rennes, Equipe Cytosquelette et Prolifération Cellulaire, Faculté de Médecine, Université de Rennes 1, 35043 Rennes, France.

Abstract:  Holoprosencephaly (HPE) is a frequent congenital malformation of the brain characterized by impaired forebrain cleavage and midline facial anomalies. Heterozygous mutations in 14 genes have been identified in HPE patients that account for only 30% of HPE cases, suggesting the existence of other HPE genes. Data from homozygosity mapping and whole-exome sequencing in a consanguineous Turkish family were combined to identify a homozygous missense mutation (c.2150G&gt;A; p.Gly717Glu) in STIL, common to the two affected children. STIL has a role in centriole formation and has previously been described in rare cases of microcephaly. Rescue experiments in U2OS cells showed that the STIL p.Gly717Glu mutation was not able to fully restore the centriole duplication failure following depletion of endogenous STIL protein indicating the deleterious role of the mutation. In situ hybridization experiments using chick embryos demonstrated that expression of Stil was in accordance with a function during early patterning of the forebrain. It is only the second time that a STIL homozygous mutation causing a recessive form of HPE was reported. This result also supports the genetic heterogeneity of HPE and increases the panel of genes to be tested for HPE diagnosis. 

Retracted: No

PubPeer comments:
 I am surprised by the neuroradiological data: ![file] The quality of cerebral MRI for patient II,3 is very poor even if the patient was 12 years-old at the time of neuroradiological examination. For example, the figure I indicate as A is probably a T1-weighted sequence but the difference between grey and white matter is impossible to assess. The figure indicated as B (that is probably a T2-weighted sequence) is really bad. It s really impossible to observe what the authors claim. The best to show a partial agenesis of the corpus callosum would be a sagittal section on T1 for example. For the second patient other sections should be necessary. A coronal section would be better for the purpose of the authors. , 
 Indeed #1 neuroradiological data are surprising. ![file] This section cannot allow to visualize a frontal horn agenesis or a double agenesis of the corpus callosum (anterior and splenium). I would be very interested to see more sections confirming this diagnosis. A sagittal section is mandatory for the corpus callosum. ![file] Semi-lobar holoprosencephaly is characterized by fusion of the frontal poles whereas the occipital ones are not. My red arrows point to frontal interhemispheric fissure, a feature that contradicts the diagnosis of the authors. Furthermore, what is the ventricular junction? This is not an anatomical terminology. It is important for the authors to consilidate their data otherwise their conclusions are completely wrong and this article should be rejected ![file] ,