title: Blood expression profiles of fragile X premutation carriers identify candidate genes involved in neurodegenerative and infertility phenotypes.
abstract: Male premutation carriers presenting between 55 and 200 CGG repeats in the Fragile-X-associated (FMR1) gene are at risk of developing Fragile X Tremor/Ataxia Syndrome (FXTAS), and females undergo Premature Ovarian Failure (POF1). Here, we have evaluated gene expression profiles from blood in male FMR1 premutation carriers and detected a strong deregulation of genes enriched in FXTAS relevant biological pathways, including inflammation, neuronal homeostasis and viability. Gene expression profiling distinguished between control individuals, carriers with FXTAS and carriers without FXTAS, with levels of expanded FMR1 mRNA being increased in FXTAS patients. In vitro studies in a neuronal cell model indicate that expression levels of expanded FMR1 5'-UTR are relevant in modulating the transcriptome. Thus, perturbations of the transcriptome may be an interplay between the CGG expansion size and FMR1 expression levels. Several deregulated genes (DFFA, BCL2L11, BCL2L1, APP, SOD1, RNF10, HDAC5, KCNC3, ATXN7, ATXN3 and EAP1) were validated in brain samples of a FXTAS mouse model. Downregulation of EAP1, a gene involved in the female reproductive system physiology, was confirmed in female carriers. Decreased levels were detected in female carriers with POF1 compared to those without POF1, suggesting that EAP1 levels contribute to ovarian insufficiency. In summary, gene expression profiling in blood has uncovered mechanisms that may underlie different pathological aspects of the premutation. A better understanding of the transcriptome dynamics in relation with expanded FMR1 mRNA expression levels and CGG expansion size may provide mechanistic insights into the disease process and a more accurate FXTAS diagnosis to the myriad of phenotypes associated with the premutation.
authors.affiliation: Genomics and Disease Group, Bioinformatics and Genomics Programme, Centre for Genomic Regulation (CRG), Barcelona 08003, Catalonia, Spain; Universitat Pompeu Fabra (UPF), Barcelona 08003, Catalonia, Spain; Hospital del Mar Medical Research Institute (IMIM), Barcelona 08003, Catalonia, Spain; CIBER de Epidemiología y Salud Pública (CIBERESP), CRG, Barcelona 08003, Catalonia, Spain.
authors.forename: Elisabet
authors.initials: E
authors.lastname: Mateu-Huertas
authors.affiliation: Biochemistry and Molecular Genetics Department, Hospital Clínic and IDIBAPS, Barcelona 08036, Catalonia, Spain; CIBER de Enfermedades Raras (CIBERER), Hospital Clínic, Barcelona 08003, Catalonia, Spain.
authors.forename: Laia
authors.initials: L
authors.lastname: Rodriguez-Revenga
authors.affiliation: Biochemistry and Molecular Genetics Department, Hospital Clínic and IDIBAPS, Barcelona 08036, Catalonia, Spain; CIBER de Enfermedades Raras (CIBERER), Hospital Clínic, Barcelona 08003, Catalonia, Spain.
authors.forename: Maria Isabel
authors.initials: MI
authors.lastname: Alvarez-Mora
authors.affiliation: Biochemistry and Molecular Genetics Department, Hospital Clínic and IDIBAPS, Barcelona 08036, Catalonia, Spain; CIBER de Enfermedades Raras (CIBERER), Hospital Clínic, Barcelona 08003, Catalonia, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Madrigal
authors.affiliation: Department of Clinical Genetics, Erasmus MC, Rotterdam 3000 DR, The Netherlands.
authors.forename: Rob
authors.initials: R
authors.lastname: Willemsen
authors.affiliation: Biochemistry and Molecular Genetics Department, Hospital Clínic and IDIBAPS, Barcelona 08036, Catalonia, Spain; CIBER de Enfermedades Raras (CIBERER), Hospital Clínic, Barcelona 08003, Catalonia, Spain.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Milà
authors.affiliation: Genomics and Disease Group, Bioinformatics and Genomics Programme, Centre for Genomic Regulation (CRG), Barcelona 08003, Catalonia, Spain; Universitat Pompeu Fabra (UPF), Barcelona 08003, Catalonia, Spain; Hospital del Mar Medical Research Institute (IMIM), Barcelona 08003, Catalonia, Spain; CIBER de Epidemiología y Salud Pública (CIBERESP), CRG, Barcelona 08003, Catalonia, Spain. Electronic address: eulalia.marti@crg.cat.
authors.forename: Eulàlia
authors.initials: E
authors.lastname: Martí
authors.affiliation: Genomics and Disease Group, Bioinformatics and Genomics Programme, Centre for Genomic Regulation (CRG), Barcelona 08003, Catalonia, Spain; Universitat Pompeu Fabra (UPF), Barcelona 08003, Catalonia, Spain; Hospital del Mar Medical Research Institute (IMIM), Barcelona 08003, Catalonia, Spain; CIBER de Epidemiología y Salud Pública (CIBERESP), CRG, Barcelona 08003, Catalonia, Spain. Electronic address: xavier.estivill@crg.cat.
authors.forename: Xavier
authors.initials: X
authors.lastname: Estivill
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics*; D006801:Humans; D007246:Infertility / Q000235:genetics*; D008297:Male; D051379:Mice; D046228:Microarray Analysis; D008840:Microfilament Proteins; D008875:Middle Aged; D009447:Neuroblastoma / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000097:blood* / Q000235:genetics; D010641:Phenotype; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D064249:Securin / Q000235:genetics / Q000378:metabolism; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D008840:Microfilament Proteins; D011506:Proteins; D064249:Securin; C497683:FMR1 protein, human; C500687:POF1B protein, human; C578002:pituitary tumor-transforming protein 1, human
keywords: Early at menopause 1 (EAP1); Fragile X Tremor/Ataxia Syndrome; Fragile X associated Premature Ovarian Insufficiency; Histone deacetylase 5 (HDAC5)