SLC9A6 mutations cause X-linked mental retardation, microcephaly, epilepsy, and ataxia, a phenotype mimicking Angelman syndrome

Abstract

Linkage analysis and DNA sequencing in a family exhibiting an X-linked mental retardation (XLMR) syndrome, characterized by microcephaly, epilepsy, ataxia, and absent speech and resembling Angelman syndrome, identified a deletion in the SLC9A6 gene encoding the Na(+)/H(+) exchanger NHE6. Subsequently, other mutations were found in a male with mental retardation (MR) who had been investigated for Angelman syndrome and in two XLMR families with epilepsy and ataxia, including the family designated as having Christianson syndrome. Therefore, mutations in SLC9A6 cause X-linked mental retardation. Additionally, males with findings suggestive of unexplained Angelman syndrome should be considered as potential candidates for SLC9A6 mutations.

Figure 1

Inheritance of Phenotypes Mimicking Angelman Syndrome Attributed to SLC9A6 Mutations (A) Pedigree of a Norwegian family linked to Xq24-q27.3. Affected males are indicated by filled squares, carrier females by circles containing a dot. The pictures show individual III-5 (left), aged two years, and individual III-4 (right), aged eight years, demonstrating tendency towards flexed arms, open mouth with drooling, and a happy disposition. (B) Pedigree of the Swedish family. Individual III-1, aged six years, demonstrates a happy disposition and an open mouth with drooling. (C) Pedigree of the UK family with picture of individual II-5, aged three years, demonstrating an open mouth with drooling and II-1, aged 20 years, with severe kyphoscoliosis. In (B) and (C), only individuals marked with an asterisk were tested as part of this investigation.

Figure 2

Mutations Found in SLC9A6 Sequence traces of wild-type (upper) and patient (lower) DNA, with corresponding amino acid single-letter codes. Sequences shown are from affected male patients from (A) Norwegian (Figure 1A), (B) Swedish (Figure 1B), (C) South African (Christianson et al, 1999²¹), and (D) UK (Figure 1C) families. Intronic DNA sequences are shown in lower case. Deleted or altered bases are underlined.

Figure 3

Neuroradiological Examinations (A and B) Magnetic Resonance Imaging (MRI). Saggital T1-weighted MRI examination of the brain in Norwegian patient III-2 (see Figure 1A) at age four years (0.5 Tesla) (A) and seven years (1.5 Tesla) (B), showing progressive cerebellar atrophy. (C and D) MR spectra (TE = 30 ms), also from Norwegian patient III-2 at seven years of age. Spectral peaks for inositol (Ins), choline (Cho), creatine (Cr), and N-acetylaspartate (NAA) are indicated. Increased amounts of the glutamate-glutamine complex (arrow) are suggested by the increased glutamate-glutamine:Cr ratio in the basal ganglia (C), whilst normal metabolite levels were seen in deep cerebral white matter (D). The illustrations to the right in the panels indicate the position of the voxels of interest (dimensions 2 × 2 × 2 cm).