Insertion of 16 amino acids in the BAR domain of the oligophrenin 1 protein causes mental retardation and cerebellar hypoplasia in an Italian family

Abstract

ABSTRACT:We observed a three-generation family with two maternal cousins and an uncle affected by mental retardation with cerebellar hypoplasia. X-linked inheritance and the presence of cerebellar malformation suggested a mutation in the OPHN1 gene. In fact, mutational screening revealed a 2-bp deletion that abolishes a donor splicing site, resulting in the inclusion of the initial 48 nucleotides of intron 7 in the mRNA. This mutation determines the production of a mutant oligophrenin 1 protein with 16 extra amino acids inserted in-frame in the N-terminal BAR domain. This is the first case of a mutation in OPHN1 that does not result in the production of a truncated protein or in its complete loss. OPHN1 (ARHGAP41) encodes a GTPase activating protein belonging to the GRAF subfamily characterized by an N-terminal BAR domain, followed by a pleckstrin-homology domain and the GAP domain. GRAF proteins play a role in endocytosis and are supposed to dimerize via their BAR domain, that induces membrane curvature. The extra 16 amino acids cause the insertion of 4.4 turns in the third alpha-helix of the BAR domain and apparently impair the protein function. In fact, the clinical phenotype of these patients is identical to that of patients with loss-of-function mutations.

A novel in-frame deletion affecting the BAR domain of OPHN1 in a family with intellectual disability and hippocampal alterations

“…The deletion resulted in the inclusion of the initial 48 nucleotides of intron 7 in the mRNA, determining a mutant OPHN1 with 16 extra amino acids inserted inframe in the N-terminal BAR domain. 6 So, the OPHN1 intragenic deletion we present in this study is the first description of a deletion of conserved amino acids from the BAR domain, which could provide critical insight into the function of this domain.…”

“…[4][5][6][22][23][24][25][26][27][28][29] All but one of the reported mutations are thought to result in premature stop codons and the absence of any OPHN1 protein. As the exception, Pirozzi et al 6 reported on a 2-bp OPHN1 deletion that abolishes a donor splicing site in intron 7 of OPHN1 in an Italian family segregating with ID and cerebellar hypoplasia.…”

“…Nevertheless, subsequent reports suggest that OPHN1 mutations result in a recognizable phenotype, which includes neuroradiological hallmarks such as cerebellar hypoplasia and ventriculomegaly, as well as subtle but characteristic facial features like strabismus and deep set eyes. 5,6 OPHN1 is expressed at low levels in all tissues, with a particularly higher expression in neurons during development and at later stages in highly plastic brain regions, such as the olfactory bulb and hippocampus. 4,7 OPHN1, localized both pre-and post-synaptically, is implicated in the regulation of dendritic spine morphology 8,9 and has a critical role in the activity-dependent maturation and plasticity of excitatory synapses by controlling their structural and functional stability.…”

Oligophrenin-1: the link between calcium-regulated exocytosis and compensatory endocytosis in neuroendocrine cells

“…The next challenges will be to decipher the mechanisms by which OPHN1 regulates fusion pore dynamics and to further explore the importance of the OPHN1 BAR domain in endocytic processes. Genetic mutations in OPHN1 gene leading either to the deletion of the BAR domain or to a non-functional BAR domain have recently been reported in patient with an intellectual disability [30,31] . Along this same line, it would be of primary interest to investigate whether, patients with mutations in the OPHN1 gene display neuroendocrine disorders in addition to neuronal defects and associated cognitive disabilities.…”

No association between FGD1 gene polymorphisms and intellectual developmental disability in the Qinba mountain area

“…Alterations of several genes in the Rho signaling pathway have been shown to contribute to intellectual developmental disorders (IDD) (Crespi et al, 2010), such as oligophrenin-1 (Nadif Kasri et al, 2009;Pirozzi et al, 2011), ARHGEF6 (Node-Langlois et al, 2006Ramakers et al, 2012), PAK3 (Node-Langlois et al, 2006), IL1RAP1 (Franek et al, 2011;Valnegri et al, 2011), TM4SF2 (Gomot et al, 2002;Noor et al, 2009), RSK2 (Jurkiewicz et al, 2010;Tejada et al, 2011), and FGD1 (Lebel et al, 2002;Kleefstra and Hamel, 2005;Dierssen and Ramakers, 2006;Kaname et al, 2006). As reported previously, abnormalities in the FGD1 gene may lead to faciogenital dysplasia and X-linked IDD (Pasteris and Gorski, 1999).…”