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J Hum Genet. 2016 May;61(5):395-403. doi: 10.1038/jhg.2015.160. Epub 2016 Jan 7.

A patient with a novel homozygous missense mutation in FTO and concomitant nonsense mutation in CETP.

Author information

1
Departments of Neurosurgery, Neurobiology and Genetics, Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, CT, USA.
2
Department of Medical Genetics, School of Medicine, Istanbul Bilim University, Istanbul, Turkey.
3
Division of Genetics, Department of Pediatrics, Istanbul University Cerrahpasa Faculty of Medicine, Istanbul, Turkey.
4
Yale Center for Genomic Analysis, Yale University School of Medicine, New Haven, CT, USA.
5
Department of Genetics, Center for Human Genetics and Genomics and Program on Neurogenetics, Yale School of Medicine, New Haven, CT, USA.

Abstract

The fat mass and obesity associated (FTO) gene has previously been associated with a variety of diseases and conditions, notably obesity, acute coronary syndrome and metabolic syndrome. Reports describing mutations in FTO as well as in FTO animal models have further demonstrated a role for FTO in the development of the brain and other organs. Here, we describe a patient born of consanguineous union who presented with microcephaly, developmental delay, behavioral abnormalities, dysmorphic facial features, hypotonia and other various phenotypic abnormalities. Whole-exome sequencing revealed a novel homozygous missense mutation in FTO and a nonsense mutation in the cholesteryl ester transfer protein (CETP). Exome copy number variation analysis revealed no disease-causing large duplications or deletions within coding regions. Patient's, her parents' and non-related control' fibroblasts were analyzed for morphologic defects, abnormal proliferation, apoptosis and transcriptome profile. We have shown that FTO is located in the nucleus of cells from each tested sample. Western blot analysis demonstrated no changes in patient FTO. Quantitative (qPCR) analysis revealed slightly decreased levels of FTO expression in patient cells compared with controls. No morphological or proliferation differences between the patient and control fibroblasts were observed. There is still much to be learned about the molecular mechanisms by which mutations in FTO contribute to such severe phenotypes.

PMID:
26740239
PMCID:
PMC4880488
DOI:
10.1038/jhg.2015.160
[Indexed for MEDLINE]
Free PMC Article

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