Integrin alpha 8 recessive mutations are responsible for bilateral renal agenesis in humans

Am J Hum Genet. 2014 Feb 6;94(2):288-94. doi: 10.1016/j.ajhg.2013.12.017.

Camille Humbert ¹, Flora Silbermann ¹, Bharti Morar ², Mélanie Parisot ³, Mohammed Zarhrate ⁴, Cécile Masson ⁵, Frédéric Tores ⁵, Patricia Blanchet ⁶, Marie-José Perez ⁶, Yuliya Petrov ⁷, Philippe Khau Van Kien ⁷, Joelle Roume ⁸, Brigitte Leroy ⁹, Olivier Gribouval ¹, Luba Kalaydjieva ², Laurence Heidet ¹⁰, Rémi Salomon ¹¹, Corinne Antignac ¹², Alexandre Benmerah ¹, Sophie Saunier ¹, Cécile Jeanpierre ¹³

Affiliations

1 Institut National de la Santé et de la Recherche Médicale U983, Hôpital Necker-Enfants Malades, 75015 Paris, France; Université Paris Descartes - Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France.
2 Harry Perkins Institute of Medical Research/Centre for Medical Research, The University of Western Australia, Perth, Nedlands, WA 6009, Australia.
3 Institut National de la Santé et de la Recherche Médicale U983, Hôpital Necker-Enfants Malades, 75015 Paris, France; Plateforme de Génomique, Institut Imagine, Hôpital Necker-Enfants Malades, 75015 Paris, France.
4 Plateforme de Génomique, Institut Imagine, Hôpital Necker-Enfants Malades, 75015 Paris, France.
5 Plateforme de Bioinformatique, Université Paris Descartes - Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France.
6 Département de Génétique Médicale, Hôpital Arnaud de Villeneuve, 34090 Montpellier, France.
7 Unité de Génétique Médicale et de Cytogénétique, Centre de Référence Anomalies du Développement et Syndromes Malformatifs, CHU de Nîmes-Hôpital Carémeau, 30029 Nîmes, France.
8 Unité de Génétique Médicale, Service de Cytogénétique et de Biologie de la Reproduction, CHI Poissy - St Germain-en-Laye, 78300 Poissy, France.
9 Service d'Anatomie et de Cytologie Pathologiques, CHI Poissy - St Germain-en-Laye, 78300 Poissy, France.
10 Assistance Publique - Hôpitaux de Paris, Centre de Référence MARHEA, Service de Néphrologie Pédiatrique, Hôpital Necker-Enfants Malades, 75015 Paris, France.
11 Institut National de la Santé et de la Recherche Médicale U983, Hôpital Necker-Enfants Malades, 75015 Paris, France; Université Paris Descartes - Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France; Assistance Publique - Hôpitaux de Paris, Centre de Référence MARHEA, Service de Néphrologie Pédiatrique, Hôpital Necker-Enfants Malades, 75015 Paris, France.
12 Institut National de la Santé et de la Recherche Médicale U983, Hôpital Necker-Enfants Malades, 75015 Paris, France; Université Paris Descartes - Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France; Assistance Publique - Hôpitaux de Paris, Service de Génétique, Hôpital Necker-Enfants Malades, 75015 Paris, France.
13 Institut National de la Santé et de la Recherche Médicale U983, Hôpital Necker-Enfants Malades, 75015 Paris, France; Université Paris Descartes - Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France. Electronic address: [email protected].

PMID: 24439109 DOI: 10.1016/j.ajhg.2013.12.017

Abstract

Renal hypodysplasia (RHD) is a heterogeneous condition encompassing a spectrum of kidney development defects including renal agenesis, hypoplasia, and (cystic) dysplasia. Heterozygous mutations of several genes have been identified as genetic causes of RHD with various severity. However, these genes and mutations are not associated with bilateral renal agenesis, except for RET mutations, which could be involved in a few cases. The pathophysiological mechanisms leading to total absence of kidney development thus remain largely elusive. By using a whole-exome sequencing approach in families with several fetuses with bilateral renal agenesis, we identified recessive mutations in the Integrin α8-encoding gene ITGA8 in two families. Itga8 homozygous knockout in mice is known to result in absence of kidney development. We provide evidence of a damaging effect of the human ITGA8 mutations. These results demonstrate that mutations of ITGA8 are a genetic cause of bilateral renal agenesis and that, at least in some cases, bilateral renal agenesis is an autosomal-recessive disease.

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