AGTR2 in brain development and function.

In the report by Huang and coworkers [Huang et al., 2005], the authors have tested four previously identified AGTR2 gene alterations [Vervoort et al., 2002] in two presumed control groups: 673 adult males and 445 females tested for hereditary hemochromatosis (HH). They have also screened 608 males (presumably mentally retarded) and 616 female patients (presumably receiving carrier testing for fragile X and of normal intelligence), all negative for the FMR1 expansion. Huang and coworkers identified the 395/402delT mutation in two of 673 HH male samples, one of 445 HH female samples, none of the FMR1 negative males, and none of the FMR1 negative females [Huang et al., 2005]. The authors consider this finding to be inconsistent with this mutation being pathogenic, even though it causes a frameshift and a truncated protein, which is deleterious in males, who carry only one copy of the gene. Without any clinical information, the assumption made by the authors that all the males and females submitted for hemochromatosis testing are likely cognitively normal is rather speculative. Several studies suggest that 1−3% of the population has some cognitive deficit and the prevalence of X-linked mental retardation (XLMR) has been estimated as approximately 1.8/1,000 males with a carrier frequency of 2.4/1,000 females [Herbst and Miller, 1980; Leonard and Wen, 2002]. Thus a possibility certainly exists that some individuals in the HH population have some degree of cognitive impairment (IQ <70). Since an alteration of the AGTR2 gene may also cause a variable effect on the cognitive function in an individual, as seen in other cases of MR genes, it is important that any individual with an AGTR2 alteration be assessed for cognitive function.