A loss‐of‐function mutation in the SLC9A6 gene causes X‐linked mental retardation resembling Angelman syndrome

Abstract

SLC9A6 mutations have been reported in families in whom X-linked mental retardation (XMR) mimics Angelman syndrome (AS). However, the relative importance of SLC9A6 mutations in patients with an AS-like phenotype or XMR has not been fully investigated. Here, the involvement of SLC9A6 mutations in 22 males initially suspected to have AS but found on genetic testing not to have AS (AS-like cohort), and 104 male patients with XMR (XMR cohort), was investigated. A novel SLC9A6 mutation (c.441delG, p.S147fs) was identified in one patient in the AS-like cohort, but no mutation was identified in XMR cohort, suggesting mutations in SLC9A6 are not a major cause of the AS-like phenotype or XMR. The patient with the SLC9A6 mutation showed the typical AS phenotype, further demonstrating the similarity between patients with AS and those with SLC9A6 mutations. To clarify the effect of the SLC9A6 mutation, we performed RT-PCR and Western blot analysis on lymphoblastoid cells from the patient. Expression of the mutated transcript was significantly reduced, but was restored by cycloheximide treatment, indicating the presence of nonsense mediated mRNA decay. Western blot analysis demonstrated absence of the normal NHE6 protein encoded for by SLC9A6. Taken together, these findings indicate a loss-of-function mutation in SLC9A6 caused the phenotype in our patient.

Emerging roles of Na+/H+ exchangers in epilepsy and developmental brain disorders

“…Patients with this condition exhibit similar symptoms to those with true Angelman syndrome, including epilepsy, ataxia, happy demeanor, drooling, and limited or absent speech, but lack UBE3 gene pathology that is characteristic of Angelman syndrome (Takahashi et al, 2011). Patients with Angelman-like syndrome can also be distinguished from Angelman patients based on their low body weight, cerebellar atrophy, and a distinct EEG pattern consisting of a 10–14 Hz background frequency.…”

SLC9/NHE gene family, a plasma membrane and organellar family of Na+/H+ exchangers

“…Diseases of the intracellular NHEs: in keeping with importance of maintenance of organellar pH, multiple neurological syndromes have been associated with consequences of disrupting functions of the intracellular NHEs, particularly NHE6 and NHE9 (Morrow et al, 2008; Gilfillan et al, 2008; Takahashi et al, 2011; Yasuda et al, 2011; Roxrud et al, 2009). The specific associations include: SLC9A9 : mutations are possibly involved in familial autism although some studies did not find an association and there is also a possible association with attention deficit hyperactivity disorder; SLC9A6 : multiple cases of X-linked mental retardation resembling Angelman syndrome and Christianson sub type have had truncation, deletion, point mutations and exon skipping of NHE6.…”

Traditional and emerging roles for the SLC9 Na+/H+ exchangers

“…gene cause three phenotypes in humans: the most common manifestation is X-linked Angelman syndrome, characterized by intellectual disability, microcephaly, epilepsy, ataxia and behavioural abnormalities [52,163]; second, an Angelman-like syndrome known as Christianson syndrome [31] and finally a syndrome presenting with corticobasal degeneration and tau deposition with severe intellectual disability and autistic behavior [49]. found that some female carriers were mentally retarded, had learning problems or dyslexia without evidence for aberrant X-inactivation suggesting either haploinsufficieny or a dominant-negative effect in female carriers.…”