Article: Genome-Wide Scan for Copy Number Variation Association with Age at Onset of Alzheimer's Disease.Kinga Szigeti, Deepika Lal, Yanchun Li, Rachelle S Doody, Kirk Wilhelmsen, Li Yan, Song Liu, Changxing Ma[show abstract] [hide abstract]
ABSTRACT: Alzheimer's disease (AD) is a progressive neurodegenerative disease with high prevalence, which imposes a substantial public health problem. The heritability of AD is estimated at 60-80% forecasting the potential use of genetic biomarkers for risk stratification in the future. Several large scale genome-wide association studies using high frequency variants identified 10 loci accountable for only a fraction of the estimated heritability. To find the missing heritability, systematic assessment of various mutational mechanisms needs to be performed. This copy number variation (CNV) genome-wide association study with age at onset (AAO) of AD identified 5 CNV regions that may contribute to the heritability of AAO of AD. Two CNV events are intragenic causing a deletion in CPNE4. In addition, to further study the mutational load at the 10 known susceptibility loci, CNVs overlapping with these loci were also catalogued. We identified rare small events overlapping CR1 and BIN1 in AD and normal controls with opposite CNV dosage. The CR1 events are consistent with previous reports. Larger scale studies with deeper genotyping specifically addressing CNV are needed to evaluate the significance of these findings.Journal of Alzheimer's disease: JAD 11/2012; · 3.74 Impact Factor
Article: Should persons with autosomal dominant AD be included in clinical trials? Authors' response.Kinga Szigeti, Rachelle S DoodyAlzheimer's Research and Therapy 05/2011; 3(3):19.
Kinga Szigeti, Rachelle S Doody[show abstract] [hide abstract]
ABSTRACT: Alzheimer disease (AD) is a devastating neurodegenerative disease affecting 1 in 68 in the population. An arbitrary cutoff 65 years as the age of onset to distinguish between early- and late-onset AD has been proposed and has been used in the literature for decades. As the majority of patients develop AD after 65 years of age, most clinical trials address this population. While the early-onset cases represent only 1% to 6% of AD cases, this population is the active working subset and thus contributes to a higher public health burden per individual, and early-onset cases are the most devastating at the level of the individual and their families. In this review, we compare and contrast the clinical, neuropsychological, imaging, genetic, biomarker, and pathological features of these two arbitrary groups. Finally, we discuss the ethical dilemma of non-abandonment and justice as it pertains to exclusion of the early-onset AD patients from clinical trials.Alzheimer's Research and Therapy 02/2011; 3(1):4.
Article: Compound heterozygosity for loss-of-function lysyl-tRNA synthetase mutations in a patient with peripheral neuropathy.Heather M McLaughlin, Reiko Sakaguchi, Cuiping Liu, Takao Igarashi, Davut Pehlivan, Kristine Chu, Ram Iyer, Pedro Cruz, Praveen F Cherukuri, Nancy F Hansen, [......], Garth Nicholson, Charles Searby, Kevin Talbot, Jeffrey M Vance, Stephan Züchner, Kinga Szigeti, James R Lupski, Ya-Ming Hou, Eric D Green, Anthony Antonellis[show abstract] [hide abstract]
ABSTRACT: Charcot-Marie-Tooth (CMT) disease comprises a genetically and clinically heterogeneous group of peripheral nerve disorders characterized by impaired distal motor and sensory function. Mutations in three genes encoding aminoacyl-tRNA synthetases (ARSs) have been implicated in CMT disease primarily associated with an axonal pathology. ARSs are ubiquitously expressed, essential enzymes responsible for charging tRNA molecules with their cognate amino acids. To further explore the role of ARSs in CMT disease, we performed a large-scale mutation screen of the 37 human ARS genes in a cohort of 355 patients with a phenotype consistent with CMT. Here we describe three variants (p.Leu133His, p.Tyr173SerfsX7, and p.Ile302Met) in the lysyl-tRNA synthetase (KARS) gene in two patients from this cohort. Functional analyses revealed that two of these mutations (p.Leu133His and p.Tyr173SerfsX7) severely affect enzyme activity. Interestingly, both functional variants were found in a single patient with CMT disease and additional neurological and non-neurological sequelae. Based on these data, KARS becomes the fourth ARS gene associated with CMT disease, indicating that this family of enzymes is specifically critical for axon function.The American Journal of Human Genetics 10/2010; 87(4):560-6. · 10.60 Impact Factor
Anthony Antonellis, Megan Y Dennis, Grzegorz Burzynski, Jimmy Huynh, Valerie Maduro, Chani J Hodonsky, Mehrdad Khajavi, Kinga Szigeti, Sandeep Mukkamala, Seneca L Bessling, William J Pavan, Andrew S McCallion, James R Lupski, Eric D Green[show abstract] [hide abstract]
ABSTRACT: Myelin protein zero (MPZ) is a critical structural component of myelin in the peripheral nervous system. The MPZ gene is regulated, in part, by the transcription factors SOX10 and EGR2. Mutations in MPZ, SOX10, and EGR2 have been implicated in demyelinating peripheral neuropathies, suggesting that components of this transcriptional network are candidates for harboring disease-causing mutations (or otherwise functional variants) that affect MPZ expression. We utilized a combination of multi-species sequence comparisons, transcription factor-binding site predictions, targeted human DNA re-sequencing, and in vitro and in vivo enhancer assays to study human non-coding MPZ variants. Our efforts revealed a variant within the first intron of MPZ that resides within a previously described SOX10 binding site is associated with decreased enhancer activity, and alters binding of nuclear proteins. Additionally, the genomic segment harboring this variant directs tissue-relevant reporter gene expression in zebrafish. This is the first reported MPZ variant within a cis-acting transcriptional regulatory element. While we were unable to implicate this variant in disease onset, our data suggests that similar non-coding sequences should be screened for mutations in patients with neurological disease. Furthermore, our multi-faceted approach for examining the functional significance of non-coding variants can be readily generalized to study other loci important for myelin structure and function.PLoS ONE 01/2010; 5(12):e14346. · 4.09 Impact Factor