Am J Hum Genet. 2016 May 5;98(5):971-980. doi: 10.1016/j.ajhg.2016.03.004. Epub 2016 Apr 21.

Recessive and Dominant De Novo ITPR1 Mutations Cause Gillespie Syndrome.

Gerber S¹, Alzayady KJ², Burglen L³, Brémond-Gignac D⁴, Marchesin V⁵, Roche O⁴, Rio M⁶, Funalot B⁷, Calmon R⁸, Durr A⁹, Gil-da-Silva-Lopes VL¹⁰, Ribeiro Bittar MF¹⁰, Orssaud C⁴, Héron B¹¹, Ayoub E², Berquin P¹², Bahi-Buisson N¹³, Bole C¹⁴, Masson C¹⁵, Munnich A⁶, Simons M⁵, Delous M¹⁶, Dollfus H¹⁷, Boddaert N⁸, Lyonnet S¹⁸, Kaplan J¹, Calvas P¹⁹, Yule DI², Rozet JM²⁰, Fares Taie L¹.

Author information

1: Laboratory of Genetics in Ophthalmology (LGO), INSERM UMR1163, Imagine - Institute of Genetic Diseases, Paris Descartes University, 75015 Paris, France.
2: Department of Pharmacology and Physiology, University of Rochester, Rochester, NY 14526, USA.
3: Reference Center for Cerebellar Malformations and Congenital Diseases, Department of Genetics, Trousseau Hospital, AP-HP, 75012 Paris; INSERM U1141, DHU PROTECT, Robert Debré Hospital, 75019 Paris, France.
4: Department of Ophthalmology, IHU Necker-Enfants Malades, Paris Descartes University, 75015 Paris, France.
5: Epithelial biology and disease - Liliane Bettencourt Chair of Developmental Biology, INSERM UMR1163, Imagine - Institute of Genetic Diseases, Paris Descartes University, 75015 Paris, France.
6: Department of Genetics, IHU Necker-Enfants Malades, University Paris Descartes, 75015 Paris, France.
7: Department of Genetics, IHU Necker-Enfants Malades, University Paris Descartes, 75015 Paris, France; Department of Genetics, GHU Henri Mondor, 94010 Créteil, France.
8: Department of Neuroradiology, IHU Necker-Enfants Malades, Paris Descartes University, 75015 Paris, France; Image at Imagine, INSERM UMR1163, Imagine - Institute of Genetic Diseases, Paris Descartes University, 75015 Paris, France.
9: Maladies Neurodégénératives, Institut du Cerveau et de la Moëlle Epinière, CHU Paris-GH La Pitié Salpêtrière-Charles Foix, Hôpital Pitié-Salpêtrière, 75013 Paris, France.
10: Department of Medical Genetics, Faculty of Medical Sciences, University of Campinas, CEP 13083-887, Sao Paulo, Brasil.
11: Department of Neuropediatrics, Hôpital Trousseau, 75012 Paris, France; Department of Pediatrics, Hôpital Jean Verdier, 93143 Bondy, France.
12: Pôle de pédiatrie, Centre d'activité de neurologie pédiatrique, CHU d'Amiens - Hôpital Nord, 80054 Amiens, Cedex 1, France.
13: Embryology and Genetics of Human Malformation, INSERM UMR1163, Imagine - Institute of Genetic Diseases, Paris Descartes University, 75015 Paris, France.
14: Genomics Platform, INSERM UMR1163, Imagine - Institute of Genetic Diseases, Paris Descartes University, 75015 Paris, France.
15: Bioinformatics Platform, INSERM UMR1163, Imagine - Institute of Genetic Diseases, Paris Descartes University, 75015 Paris, France.
16: Laboratory of Hereditary Kidney Diseases, INSERM UMR1163, Imagine - Institute of Genetic Diseases, Paris Descartes University, 75015 Paris, France.
17: Laboratoire de Génétique Médicale, Institut de Génétique Médicale d'Alsace, INSERM U1112, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, 67085 Strasbourg, France.
18: Department of Genetics, IHU Necker-Enfants Malades, University Paris Descartes, 75015 Paris, France; Embryology and Genetics of Human Malformation, INSERM UMR1163, Imagine - Institute of Genetic Diseases, Paris Descartes University, 75015 Paris, France.
19: Service de Génétique Clinique, Hôpital Purpan, 31300 Toulouse, France.
20: Laboratory of Genetics in Ophthalmology (LGO), INSERM UMR1163, Imagine - Institute of Genetic Diseases, Paris Descartes University, 75015 Paris, France. Electronic address: jean-michel.rozet@inserm.fr.

Abstract

Gillespie syndrome (GS) is a rare variant form of aniridia characterized by non-progressive cerebellar ataxia, intellectual disability, and iris hypoplasia. Unlike the more common dominant and sporadic forms of aniridia, there has been no significant association with PAX6 mutations in individuals with GS and the mode of inheritance of the disease had long been regarded as uncertain. Using a combination of trio-based whole-exome sequencing and Sanger sequencing in five simplex GS-affected families, we found homozygous or compound heterozygous truncating mutations (c.4672C>T [p.Gln1558(∗)], c.2182C>T [p.Arg728(∗)], c.6366+3A>T [p.Gly2102Valfs5(∗)], and c.6664+5G>T [p.Ala2221Valfs23(∗)]) and de novo heterozygous mutations (c.7687_7689del [p.Lys2563del] and c.7659T>G [p.Phe2553Leu]) in the inositol 1,4,5-trisphosphate receptor type 1 gene (ITPR1). ITPR1 encodes one of the three members of the IP3-receptors family that form Ca(2+) release channels localized predominantly in membranes of endoplasmic reticulum Ca(2+) stores. The truncation mutants, which encompass the IP3-binding domain and varying lengths of the modulatory domain, did not form functional channels when produced in a heterologous cell system. Furthermore, ITPR1 p.Lys2563del mutant did not form IP3-induced Ca(2+) channels but exerted a negative effect when co-produced with wild-type ITPR1 channel activity. In total, these results demonstrate biallelic and monoallelic ITPR1 mutations as the underlying genetic defects for Gillespie syndrome, further extending the spectrum of ITPR1-related diseases.