👤 Christine K Christie

Breast cancer is a heterogeneous disease that comprises multiple histological and molecular subtypes. To gain insight into mutations that drive breast tumorigenesis, we describe a pipeline for the identification and validation of tumor suppressor genes. Based on an in vivo genome-wide CRISPR/Cas9 screen in Trp53 Show less

The contribution of polymorphisms associated with adult lipids in early life is unknown. We studied 158 adult lipid polymorphisms in 1440 participants (544 children, 544 mothers and 324 fathers) of the Family Atherosclerosis Monitoring In early life (FAMILY) birth cohort. Total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) measurements were collected at birth, 3 and 5 years of age. Polymorphisms were genotyped using the Illumina Cardio-Metabochip array. Genotype scores (GS) were calculated for TC, HDL-C, LDL-C and TG. Linear and mixed-effects regressions adjusted for sex, age and population stratification were performed. The GS was associated with LDL-C level at 3 and 5 years (β = 0.017 ± 0.003, P = 2.9 × 10 Show less

Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is a congenital visceral myopathy characterized by severe dilation of the urinary bladder and defective intestinal motility. The genetic basis of MMIHS has been ascribed to spontaneous and autosomal dominant mutations in actin gamma 2 ( Show less

Hereditary multiple exostosis (HME) is an autosomal dominant disorder characterized by the development of benign cartilage-capped tumors at the juxta-epiphyseal regions of long bones. HME is usually caused by mutations of EXT1 or EXT2. The objective of this study was to investigate a three-generation Austrian kindred with HME for EXT1 and EXT2 mutations and for abnormalities of bone mineral density (BMD). DNA sequence and mRNA analyses were used to identify the mutation and its associated consequences. Serum biochemical and radiological investigations assessed bone metabolism and BMD. HME-affected members had a lower femoral neck BMD compared with nonaffected members (z-scores, -2.98 vs. -1.30; P = 0.011), and in those less than 30 yr of age, the lumbar spine BMD was also low (z-scores, -2.68 vs. -1.42; P = 0.005). However, they had normal mobility and normal serum concentrations of calcium, phosphate, alkaline phosphatase activity, creatinine, PTH, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, osteocalcin, and beta-crosslaps. DNA sequence analysis of EXT1 revealed a heterozygous g-->c transversion that altered the invariant ag dinucleotide of the intron 8 acceptor splice site. RT-PCR analysis using lymphoblastoid RNA showed that the mutation resulted in skipping of exon 9 with a premature termination at codon 599. DNA sequence abnormalities of the osteoprotegerin gene, which is in close proximity to the EXT1 gene, were not detected. A novel heterozygous acceptor splice site mutation of EXT1 results in HME that is associated with a low peak bone mass, indicating a possible additional role for EXT1 in bone biology and in regulating BMD. Show less