Identification of two AGTR2 mutations in male patients with non-syndromic mental retardation
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- Ylisaukko-oja, T., Rehnström, K., Vanhala, R. et al. Hum Genet (2004) 114: 211. doi:10.1007/s00439-003-1048-8
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Mutations in the coding region of the angiotensin II type 2 receptor gene (AGTR2) were recently identified to cause X-linked recessive mental retardation. We report a mutation screening of the AGTR2 gene in 57 Finnish male patients with non-syndromic mental retardation. We identified two mutations, a 62G→T transversion, which leads to a substitution of glycine for valine (G21V) and a 157A→T transversion, which causes a substitution of isoleucine for phenylalanine (I53F). The patients with AGTR2 sequence variants had severe/profound mental retardation, epileptic seizures, restlessness, hyperactivity, and disturbed development of speech.
One of the recent breakthroughs in molecular genetic studies of X-linked mental retardation (MR) was the identification of the involvement of the angiotensin II type 2 receptor (AGTR2) in the aetiology of non-syndromic MR (Vervoort et al. 2002). The main biological role of AGTR2 is still unclear but several studies have indicated that some of its functions are involved in brain development (Gallinat et al. 2000; Hein et al. 1995; Ichiki et al. 1995; Okuyama et al. 1999). Further support for these results was obtained when a female patient with moderately severe MR was reported to carry a balanced X;7 translocation, which disrupted the transcription of the AGTR2 gene. The other copy of the gene was silenced by skewed X-chromosome inactivation. Screening of a cohort of 590 mentally retarded male patients resulted in the identification of eight mutations in the AGTR2 gene (1.4%), including a frame-shift mutation and three different amino acid substitutions (G21V, R324Q and I337V; Vervoort et al. 2002). The clinical features were variable and included moderate to severe MR, seizures and autistic manifestations. In a subsequent study, Bienvenu and colleagues (2003) screened 360 unrelated male patients with non-syndromic MR and found that three patients carried sequence variations in AGTR2. However, none of these variants is likely to be causal. Here, we report the mutation screening of the AGTR2 gene in 57 Finnish male patients with moderate to profound non-syndromic MR.
Patient M119 has a novel 157A→T transversion, which leads to substitution of isoleucine for phenylalanine (I53F). His healthy mother was a carrier of the mutation but other relatives were unavailable for study. The patient is a 43-year-old severely/profoundly mentally retarded man. His mother had had mild eclampsia during pregnancy. He was hypotonic from birth and learned to walk at 2 years of age. He was hyperactive and has always had sleeping problems. He has never spoken but he uses his voice and gestures to show his needs and understands simple spoken language. At 5 years of age, he was considered moderately mentally retarded.
He started to have seizures at 6 years of age. From 10 years of age, he has lived permanently in a home for the mentally retarded, because of aggressive and restless behaviour and sleep problems. At this stage, he was considered severely mentally retarded. He is mobile but requires some assistance in daily tasks. He has slight dysmorphic features, including a skull that is flattened at the back, short fingers, a broad mouth and widely spaced teeth. His electroencephalogram was abnormal, including generalized longer sharp wave (2–3 Hz) and shorter spike and sharp wave (3–4 Hz) episodes that increase during drowsiness. His skull X-ray was normal. Neither a computer tomography scan nor magnetic resonance imaging of the brain has been performed but pneumencephalography at 8 years of age showed mildly dilated ventricles.
Clinical findings of the patients with AGTR2 sequence variants
Although the clinical information in the original report is relatively scarce, some common clinical findings are evident in the patients with AGTR2 mutations described by Vervoort et al. (2002) and in those described here. Both of the patients reported here have epileptic seizures, which was found in five out of nine patients in the original study. Furthermore, disturbed development of speech was common, being present in three patients in the original report, whereas neither of the patients reported here developed speech. The degree of MR has ranged from moderate to profound. Both of our patients have exhibited hyperactivity and restlessness.
The novel mutation reported here changes isoleucine to phenylalanine within the first transmembrane domain. Both of these amino acids are hydrophobic but phenylalanine has a considerably larger aromatic side chain. AGTR1 and AGTR2 display only a 32%–34% identity at the amino acid level. The mutated isoleucine is conserved between AGTR1 and AGTR2 indicating that it might have a functional role. In contrast, this amino acid is not conserved between humans and rodents. On the other hand, several examples have shown that, even if the mutated base is rare and located on a conserved region, it may represent only a rare non-causal variant (Bienvenu et al. 2003). Consequently, functional studies are warranted to confirm the role of these variants in the pathogenesis of MR.
The frequency of mutations found in this study (3.5%) is relatively high and should be interpreted with caution because of the relatively small size of the study material. When the results obtained from the mutational analyses of AGTR2 carried out so far are combined, altogether 1007 patients have been screened with the identification of potentially pathogenic mutations in 10 individuals; this equals a frequency of ~1%. These results indicate that systematic mutation screening with larger sample sets involving segregation analyses is needed to evaluate further the frequency and mutation spectrum of AGTR2 in non-syndromic MR.
We acknowledge all the individuals who participated in this study. This work was financially supported by the Academy of Finland (LIFE 2000), by the Päivikki and Sakari Sohlberg Foundation and by Helsinki University Hospital Research Funding.