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

Abstract

Oligophrenin-1 (OPHN1) is one of at least seven genes located on chromosome X that take part in Rho GTPase-dependent signaling pathways involved in X-linked intellectual disability (XLID). Mutations in OPHN1 were primarily described as an exclusive cause of non-syndromic XLID, but the re-evaluation of the affected individuals using brain imaging displayed fronto-temporal atrophy and cerebellar hypoplasia as neuroanatomical marks. In this study, we describe clinical, genetic and neuroimaging data of a three generation Brazilian XLID family co-segregating a novel intragenic deletion in OPHN1. This deletion results in an in-frame loss of exon 7 at transcription level (c.781_891del; r.487_597del), which is predicted to abolish 37 amino acids from the highly conserved N-terminal BAR domain of OPHN1. cDNA expression analysis demonstrated that the mutant OPHN1 transcript is stable and no abnormal splicing was observed. Features shared by the affected males of this family include neonatal hypotonia, strabismus, prominent root of the nose, deep set eyes, hyperactivity and instability/ intolerance to frustration. Cranial MRI scans showed large lateral ventricles, vermis hypoplasia and cystic dilatation of the cisterna magna in all affected males. Interestingly, hippocampal alterations that have not been reported in patients with loss-of-function OPHN1 mutations were found in three affected individuals, suggesting an important function for the BAR domain in the hippocampus. This is the first description of an in-frame deletion within the BAR domain of OPHN1 and could provide new insights into the role of this domain in relation to brain and cognitive development or function.

Expanding the phenotypic spectrum associated with OPHN1 variants

“…All three patients present with psychomotor delay, hypotonia, seizures, speech delay, and ataxic gait, which is consistent with previously reported cases (Al-Owain et al 2011;Bergmann et al 2003;Billuart et al 2000;Busa et al 2017;Chabrol et al 2005;des Portes et al 2004;Madrigal et al 2008;Moortgat et al 2018;Philip et al 2003;Santos-Reboucas et al 2014;Zanni et al 2005). Additionally, two of the three probands were diagnosed with strabismus, while the third was reported to have pseudostrabismus (Table 1).…”

“…Review of the three patients' medical records revealed variability in their phenotypes in comparison to the common features reported in the literature (Table 1) (Al-Owain et al 2011;Bergmann et al 2003;Busa et al 2017;Chabrol et al 2005;des Portes et al 2004;Madrigal et al 2008;Moortgat et al 2018;Philip et al 2003;Santos-Reboucas et al 2014;Zanni et al 2005). This was particularly true for the dysmorphisms previously associated with OPHN1 variants, with Patients 2 and 3 lacking most of the previously reported common facial features (Fig.…”

“…In terms of other neurological findings, imaging for Patient 3 was negative for cerebellar hypoplasia and ventriculomegaly. None of the three patients had genitourinary features, such as hypoplastic scrotum, microphallus, cryptorchidism, which had previously been associated with the OPHN1 variants (Al-Owain et al 2011;Bergmann et al 2003;Busa et al 2017;Chabrol et al 2005;des Portes et al 2004;Madrigal et al 2008;Moortgat et al 2018;Philip et al 2003;Santos-Reboucas et al 2014;Zanni et al 2005) (Table 1).…”

“…1(1a-1b, 4a-4b)) ( Fig. 2A) (Al-Owain et al 2011;Bergmann et al 2003;Billuart et al 1998;Billuart et al 2000;Busa et al 2017;Chabrol et al 2005;Classen et al 2013;des Portes et al 2004;Madrigal et al 2008;Philip et al 2003;Santos-Reboucas et al 2014;Zanni et al 2005) (OMIM300486). After almost two decades of inconclusive testing and misdiagnoses, this individual had been referred to the GDC with a leading clinical diagnosis of Cohen syndrome (OMIM216550), although he lacked central obesity.…”

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.…”