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PLoS One. 2015 Feb 6;10(2):e0117418. doi: 10.1371/journal.pone.0117418. eCollection 2015.

Homozygous STIL mutation causes holoprosencephaly and microcephaly in two siblings.

Author information

1
Institut de Génétique et Développement de Rennes, Equipe Génétique des Pathologies Liées au Développement, Faculté de Médecine, Université de Rennes 1, 35043 Rennes, France.
2
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.
3
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.
4
Laboratoire de Génétique Moléculaire et Génomique, CHU Pontchaillou, 35033 Rennes, France.
5
Inserm U946, Variabilité Génétique et Maladies Humaines, Université Paris-Diderot, 75010 Paris, France.
6
Service de Génétique Clinique, Hôpital Sud, 35200 Rennes, France.
7
Service de Pédiatrie, Hôpital Jean Verdier, APHP, 93140 Bondy, France.
8
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.
9
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>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.

PMID:
25658757
PMCID:
PMC4319975
DOI:
10.1371/journal.pone.0117418
[Indexed for MEDLINE]
Free PMC Article

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