Duplication of RPS6KA3 gene produces limited family intellectual disability

The financial contributions made some years ago by individuals and public administration bodies in the telemarathon solidarity events on the Basque Public Broadcasting Corporation (EiTB) and subsequently channelled through the Basque Foundation for Health Innovation and Research (BIOEF), has resulted in undertaking successful innovative research at the Cruces Hospital near Bilbao in the Basque province of Bizkaia, describing a new syndrome of limited family intellectual disability.

The team led by geneticist Isabel Tejada described for the first time to the world that the duplication of the RPS6KA3 gene produces a limited intellectual disability in asymptomatic mothers who are carriers. This gene is found on the X chromosome, and one that has made the genetics laboratory at the Bizkaian hospital a reference at an international level. The complete research was published in the scientific journal Paediatrics.

This discovery turns out to be especially relevant because, although the genetic causes of serious intellectual disability has a wealth of research literature, "in cases of slight or limited intellectual disability, the genetic causes are only known in a small percentage of cases", pointed out Ms Tejada, in charge of the Molecular Genetics Laboratory at the Cruces Hospital and the research leader.

The research was initiated when a mother attended a neuropaediatric clinic with a child who had psychomotor retardation which he had had since the first year of life, "although without any facial dysmorphia or associated anomalies", and was referred to the genetics laboratory for case study. The patient had two maternal uncles who also had psychomotor impairment and who had been unable to complete primary school education, although they lived self-sufficiently.

"A karyotype or chromosomal X-fragile syndrome and a molecular study" were carried out on the patient. But, in the absence of a positive result being registered for these tests and with a family history, the scientists decided to continue the research.

At this point the exploration of other genes on the X chromosome became necessary, a task which was able to be carried out thanks to two research projects initiated by the Basque Foundation for Health Innovation and Research, employing the income obtained from the telemarathon solidarity events of the Basque Public Broadcasting Corporation some years ago and which was channelled into research into limited intellectual disability and rare diseases.

The team led by Isabel Tejada then decided to apply a technique known as CNV (copy number variants), "observing deletions and duplications of the genome not visible with the microscope". To this end, "we used a a technique known as MLPA (Multiplex ligation-dependent probe amplification) involving a number of probes or fragments of the genome we wished to analyse, given that there had been three known similar cases with the common factor of maternal inheritance. To our surprise we spotted a duplication of a very small region, hitherto undescribed, and which contained 7 genes of which only one - the RPS6KA3 - is related to mental retardation", pointed out the geneticist.

Nevertheless, mutations in this gene produce another type of syndrome which was not the case in this patient. "This fact made us think that we had something novel in front of us and that, as happens with other syndromes, the duplication of the gene or genes produces a pathological effect opposite to and/or different from isolated deletions or mutations, given that it is not the deficiency of one or various proteins, but their over-expression, that produces the pathological effect".

Finally, the hypothesis was tested "with other, complementary tests, such as CGH (comparative genomic hybridisation) arrays and studies of messenger RNA and protein expression".