Novel intragenic deletion in OPHN1 in a family causing XLMR with cerebellar hypoplasia and distinctive facial appearance

Abstract

X-linked mental retardation (XLMR) is notably a heterogeneous condition and often poses a diagnostic challenge. The oligophrenin 1 gene (OPHN1) is a protein with a Rho-GTPase-activating domain required in the regulation of the G-protein cycle. Mutations in the OPHN1 cause XLMR with cerebellar hypoplasia and distinctive facial appearance. We report a large Saudi family of four boys and one girl affected with XLMR. The boys had moderate MR, seizure disorder, facial dysmorphism, and cerebellar vermis hypoplasia. The girl had mild MR, seizures, and mild cerebellar hypoplasia. A novel deletion of at least exons 7-15 was identified by polymerase chain reaction analysis and multiple ligation probe amplification of the OPHN1 gene. The array comparative genomic hybridization further delineated approximately 68 kb deletion of the 7-15 exons and nearly half of intron 15. In addition, the X-inactivation confirmed random pattern in the girl. Although the affected boys have remarkably similar phenotype, there was some variability in the severity of the seizure disorder and the cerebellar hypoplasia. The report confirms the previous findings that carrier females may be symptomatic.

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

“…Intrafamiliar phenotypic variability for OPHN1 mutations has previously been described for affected males 5 as well as for carrier females, who usually present a mild phenotype with minor cognitive delay and subtle facial dysmorphies with or without brain abnormalities. 3,5,[23][24][25]27 The absence of other discernible symptoms and signs among ID patients with OPHN1 mutations suggests that an OPHN1 deficiency may be compensated by functional redundancy with other Rho GTPase-related proteins in non-affected tissues.…”

“…[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.…”

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

“…Des Portes et al (2004) carefully investigated the brain structure of these patients and described a specific dysgenesis of the cerebellar vermis and some diffuse cortico-subcortical atrophy. Thirteen more pedigrees with mutations in OPHN1 have been reported since 1998 (Tentler et al, 1999;Bergmann et al, 2003;Philip et al, 2003;Chabrol et al, 2005;Zanni et al, 2005;Menten et al, 2007;Froyen et al, 2007;Madrigal et al, 2008;Al Owain et al, 2010). All the investigated patients had some degree of cerebellar hypoplasia with the exception of a female patient with mild mental retardation (IQ~75) in the pedigree reported by Bergmann et al (2003).…”

“…The same gene was interrupted in a female patient with an X;12 balanced translocation (Bienvenu et al, 1997;Billuart et al, 1998). After these two reports, 13 more pedigrees have been reported with mutations in OPHN1 (Tentler et al, 1999;Bergmann et al, 2003;Philip et al, 2003;Chabrol et al, 2005;Zanni et al, 2005;Menten et al, 2007;Froyen et al, 2007;Madrigal et al, 2008;Al Owain et al, 2010). All OPHN1 mutations identified to date eventually cause loss of function of the oligophrenin 1 protein.…”