Loss of LDAH associated with prostate cancer and hearing loss
Year: 2018
Type: article
Abstract: Great strides in gene discovery have been made using a multitude of methods to associate phenotypes with genetic variants, but there still remains a substantial gap between observed symptoms and identified genetic defects. Herein, we use the convergence of various genetic and genomic techniques to investigate the underpinnings of a constellation of phenotypes that include prostate cancer (PCa) and sensorineural hearing loss (SNHL) in a human subject. Through interrogation of the subject's de novo, germline, balanced chromosomal translocation, we first identify a correlation between his disorders and a poorly annotated gene known as lipid droplet associated hydrolase (LDAH). Using data repositories of both germline and somatic variants, we identify convergent genomic evidence that substantiates a correlation between loss of LDAH and PCa. This correlation is validated through both in vitro and in vivo models that show loss of LDAH results in increased risk of PCa and, to a lesser extent, SNHL. By leveraging convergent evidence in emerging genomic data, we hypothesize that loss of LDAH is involved in PCa and other phenotypes observed in support of a genotype-phenotype association in an n-of-one human subject.
Source: Human Molecular Genetics
DOI: 10.1093/hmg/ddy310
Authors: Benjamin B Currall, Ming Chen, Richard C Sallari, Maura Cotter, Kristen E Wong, Nahid G Robertson, Kathryn L Penney, Andrea Lunardi, Markus Reschke, Ann E Hickox, Yanbo Yin, Garrett T Wong, Jacqueline Fung, Kerry K Brown, Robin E Williamson, Nicholas A Sinnott-Armstrong, Tammy Kammin, Andrew Ivanov, Cinthya J Zepeda-Mendoza, Jun Shen, Bradley J Quade, Sabina Signoretti, Kathleen S Arnos, Alexander S Banks, Nikolaos Patsopoulos, M Charles Liberman, Manolis Kellis, Pier Paolo Pandolfi, Cynthia C Morton
Institutions: Brigham and Women's Hospital, Harvard University, Beth Israel Deaconess Medical Center, Broad Institute, MIT Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Dana-Farber Cancer Institute, Massachusetts Eye and Ear Infirmary, Harvard–MIT Division of Health Sciences and Technology, Gallaudet University, Manchester Academic Health Science Centre, University of Manchester
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: University of California, Santa Cruz, Harvard Medical School, Giovanni Armenise-Harvard Foundation, National Institutes of Health, National Cancer Institute, National Institute on Deafness and Other Communication Disorders, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: G1126345087, G1677357873, G2076293524, Core Support for Hearing Research - "NIDCD" Research Core Center P30, G3642634010, Understanding the Role of C2orf43 in Hearing Loss, G5847736901, Cytogenetic Approaches to Finding Auditory Genes, Hearing loss associated with chromosomal rearrangements, SPORE in Prostate Cancer, Cochlear synaptopathy in noise-induced and age-related hearing loss: mechanisms and treatments, Training Grant in Genetics
OpenAlex ID: W2889182746