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  • 1
    Keywords: GENES ; PROJECT ; OF-THE-LITERATURE ; FAMILIES ; EPISPADIAS COMPLEX BEEC ; imputation ; DYSREGULATION ; GUDMAP ; SALL1 ; PLAYS
    Abstract: Bladder exstrophy-epispadias complex (BEEC), the severe end of the urorectal malformation spectrum, has a profound impact on continence as well as sexual and renal functions. It is widely accepted that for the majority of cases the genetic basis appears to be multifactorial. Here, we report the first study which utilizes genome-wide association methods to analyze a cohort comprising patients presenting the most common BEEC form, classic bladder exstrophy (CBE), to identify common variation associated with risk for isolated CBE. We employed discovery and follow-up samples comprising 218 cases/865 controls and 78 trios in total, all of European descent. Our discovery sample identified a marker near SALL1, showing genome-wide significant association with CBE. However, analyses performed on follow-up samples did not add further support to these findings. We were also able to identify an association with CBE across our study samples (discovery: P = 8.88 x 10(-5); follow-up: P = 0.0025; combined: 1.09 x 10(-6)) in a highly conserved 32 kb intergenic region containing regulatory elements between WNT3 and WNT9B. Subsequent analyses in mice revealed expression for both genes in the genital region during stages relevant to the development of CBE in humans. Unfortunately, we were not able to replicate the suggestive signal for WNT3 and WNT9B in a sample that was enriched for non-CBE BEEC cases (P = 0.51). Our suggestive findings support the hypothesis that larger samples are warranted to identify association of common variation with CBE.
    Type of Publication: Journal article published
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  • 2
    Publication Date: 2014-03-15
    Description: Motor neurons, which relay neural commands to drive skeletal muscle movements, encompass types ranging from "slow" to "fast," whose biophysical properties govern the timing, gradation, and amplitude of muscle force. Here we identify the noncanonical Notch ligand Delta-like homolog 1 (Dlk1) as a determinant of motor neuron functional diversification. Dlk1, expressed by ~30% of motor neurons, is necessary and sufficient to promote a fast biophysical signature in the mouse and chick. Dlk1 suppresses Notch signaling and activates expression of the K(+) channel subunit Kcng4 to modulate delayed-rectifier currents. Dlk1 inactivation comprehensively shifts motor neurons toward slow biophysical and transcriptome signatures, while abolishing peak force outputs. Our findings provide insights into the development of motor neuron functional diversity and its contribution to the execution of movements.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Muller, Daniel -- Cherukuri, Pitchaiah -- Henningfeld, Kristine -- Poh, Chor Hoon -- Wittler, Lars -- Grote, Phillip -- Schluter, Oliver -- Schmidt, Jennifer -- Laborda, Jorge -- Bauer, Steven R -- Brownstone, Robert M -- Marquardt, Till -- R01 HD042013/HD/NICHD NIH HHS/ -- Canadian Institutes of Health Research/Canada -- New York, N.Y. -- Science. 2014 Mar 14;343(6176):1264-6. doi: 10.1126/science.1246448.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Developmental Neurobiology Laboratory, European Neuroscience Institute (ENI-G), Grisebachstrasse 5, 37077 Gottingen, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24626931" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Gene Expression Regulation ; Intercellular Signaling Peptides and Proteins/genetics/*physiology ; Mice ; Mice, Knockout ; Motor Neurons/*metabolism ; Movement ; Muscle Fibers, Skeletal/physiology ; Muscle, Skeletal/innervation/*physiology ; Potassium Channels, Voltage-Gated/genetics ; Receptors, Notch/*physiology ; Signal Transduction ; Transcriptome
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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