Activation Ratio Correlates with IQ in Female Carriers of the <i>FMR1</i> Premutation
Dragana Protic,
Roberta Polli,
Ye Hyun Hwang,
Guadalupe Mendoza,
Randi Hagerman,
Blythe Durbin-Johnson,
Bruce E. Hayward,
Karen Usdin,
Alessandra Murgia,
Flora Tassone
Affiliations
Dragana Protic
Department of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
Roberta Polli
Laboratory of Molecular Genetics of Neurodevelopment, Department of Woman and Child Health, University of Padova, 35128 Padova, Italy
Ye Hyun Hwang
Department of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Sacramento, CA 95817, USA
Guadalupe Mendoza
Department of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Sacramento, CA 95817, USA
Randi Hagerman
Medical Investigation of Neurodevelopmental Disorders (MIND) Institute UCDH, University of California Davis, Sacramento, CA 95817, USA
Blythe Durbin-Johnson
Department of Public Health Sciences, Division of Biostatistics, University of California, Davis, CA 95616, USA
Bruce E. Hayward
Laboratory of Cell and Molecular Biology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
Karen Usdin
Laboratory of Cell and Molecular Biology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
Alessandra Murgia
Laboratory of Molecular Genetics of Neurodevelopment, Department of Woman and Child Health, University of Padova, 35128 Padova, Italy
Flora Tassone
Department of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Sacramento, CA 95817, USA
Carriers of the FMR1 premutation (PM) allele are at risk of one or more clinical conditions referred to as FX premutation-associated conditions (FXPAC). Since the FMR1 gene is on the X chromosome, the activation ratio (AR) may impact the risk, age of onset, progression, and severity of these conditions. The aim of this study was to evaluate the reliability of AR measured using different approaches and to investigate potential correlations with clinical outcomes. Molecular and clinical assessments were obtained for 30 PM female participants, and AR was assessed using both Southern blot analysis (AR-Sb) and methylation PCR (AR-mPCR). Higher ARs were associated with lower FMR1 transcript levels for any given repeat length. The higher AR-Sb was significantly associated with performance, verbal, and full-scale IQ scores, confirming previous reports. However, the AR-mPCR was not significantly associated (p > 0.05) with these measures. Similarly, the odds of depression and the number of medical conditions were correlated with higher AR-Sb but not correlated with a higher AR-mPCR. This study suggests that AR-Sb may be a more reliable measure of the AR in female carriers of PM alleles. However, further studies are warranted in a larger sample size to fully evaluate the methylation status in these participants and how it may affect the clinical phenotype.
