title: The genomic architecture of NLRP7 is Alu rich and predisposes to disease-associated large deletions.
abstract: NLRP7 is a major gene responsible for recurrent hydatidiform moles. Here, we report 11 novel NLRP7 protein truncating variants, of which five deletions of more than 1-kb. We analyzed the transcriptional consequences of four variants. We demonstrate that one large homozygous deletion removes NLRP7 transcription start site and results in the complete absence of its transcripts in a patient in good health besides her reproductive problem. This observation strengthens existing data on the requirement of NLRP7 only for female reproduction. We show that two other variants affecting the splice acceptor of exon 6 lead to its in-frame skipping while another variant affecting the splice donor site of exon 9 leads to an in-frame insertion of 54 amino acids. Our characterization of the deletion breakpoints demonstrated that most of the breakpoints occurred within Alu repeats and the deletions were most likely mediated by microhomology events. Our data define a hotspot of Alu instability and deletions in intron 5 with six different breakpoints and rearrangements. Analysis of NLRP7 genomic sequences for repetitive elements demonstrated that Alu repeats represent 48% of its intronic sequences and these repeats seem to have been inserted into the common NLRP2/7 primate ancestor before its duplication into two genes.
authors.affiliation: Department of Human Genetics, McGill University Health Centre Research Institute, Montréal, Canada.|Department of Obstetrics and Gynaecology, McGill University Health Centre Research Institute, Montréal, Canada.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Reddy
authors.affiliation: Department of Human Genetics, McGill University Health Centre Research Institute, Montréal, Canada.|Department of Obstetrics and Gynaecology, McGill University Health Centre Research Institute, Montréal, Canada.
authors.forename: Ngoc M P
authors.initials: NM
authors.lastname: Nguyen
authors.affiliation: Laboratoire de Génétique des Maladies Rares et Autoinflammatoires, Hôpital Arnaud de Villeneuve, Montpellier, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Sarrabay
authors.affiliation: Genetics Department, Shiraz University of Medical Sciences, Shiraz, Iran.
authors.forename: Maryam
authors.initials: M
authors.lastname: Rezaei
authors.affiliation: Hospital Aranda de la Parra, Laboratorio-sótano, Hidalgo, Centro Leon Gto, Mexico.
authors.forename: Mayra C G
authors.initials: MC
authors.lastname: Rivas
authors.affiliation: Ege University Medical Faculty, Department of Medical Genetics, Izmir, Turkey.
authors.forename: Aysenur
authors.initials: A
authors.lastname: Kavasoglu
authors.affiliation: Genetiks Genetic Laboratory, Istanbul, Turkey.
authors.forename: Hakan
authors.initials: H
authors.lastname: Berkil
authors.affiliation: Kuwait Medical Genetic Center, Kuwait Pediatric Department, Kuwait City, Kuwait.
authors.forename: Alaa
authors.initials: A
authors.lastname: Elshafey
authors.forename: Ebtesam
authors.initials: E
authors.lastname: Abdalla
authors.affiliation: Division of Maternal-Fetal Medicine, Comprehensive Hemostasis & Thrombosis Center, Duke University Medical Centre, Durham, NC, USA.
authors.forename: Kristin P
authors.initials: KP
authors.lastname: Nunez
authors.affiliation: Institut Ste Catherine, Avignon, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Dreyfus
authors.affiliation: Gynecologic and Obstetrics, Department University Hospital Amiens, Amiens, France.
authors.forename: Merviel
authors.initials: M
authors.lastname: Philippe
authors.affiliation: Medical Genetics Department, Sarem Fertility & Infertility Research Center (SAFIR), Tehran, Iran.
authors.forename: Zahra
authors.initials: Z
authors.lastname: Hadipour
authors.affiliation: Ege University Medical Faculty, Department of Medical Genetics, Izmir, Turkey.
authors.forename: Asude
authors.initials: A
authors.lastname: Durmaz
authors.affiliation: Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, The University of North Carolina, Chapel Hill, USA.
authors.forename: Erin E
authors.initials: EE
authors.lastname: Eaton
authors.affiliation: Division of Maternal-Fetal Medicine, Comprehensive Hemostasis & Thrombosis Center, Duke University Medical Centre, Durham, NC, USA.
authors.forename: Brittany
authors.initials: B
authors.lastname: Schubert
authors.affiliation: Department of Obstetrics and Gynaecology, Oncology Unit, Kanuni Sultan Suleyman Training and Research Hospital, Istanbul, Turkey.
authors.forename: Volkan
authors.initials: V
authors.lastname: Ulker
authors.affiliation: Medical Genetics Department, Sarem Fertility & Infertility Research Center (SAFIR), Tehran, Iran.
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Hadipour
authors.affiliation: Genetics Department, Shiraz University of Medical Sciences, Shiraz, Iran.
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Ahmadpour
authors.affiliation: Laboratoire de Génétique des Maladies Rares et Autoinflammatoires, Hôpital Arnaud de Villeneuve, Montpellier, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Touitou
authors.affiliation: Genetics Department, Shiraz University of Medical Sciences, Shiraz, Iran.
authors.forename: Majid
authors.initials: M
authors.lastname: Fardaei
authors.affiliation: Department of Human Genetics, McGill University Health Centre Research Institute, Montréal, Canada.|Department of Obstetrics and Gynaecology, McGill University Health Centre Research Institute, Montréal, Canada.
authors.forename: Rima
authors.initials: R
authors.lastname: Slim
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D020087:Alu Elements / Q000235:genetics*; D056905:Chromosome Breakpoints; D019143:Evolution, Molecular; D005091:Exons; D005260:Female; D017353:Gene Deletion; D006801:Humans; D006828:Hydatidiform Mole / Q000175:diagnosis / Q000235:genetics*; D016254:Mutagenesis, Insertional; D011247:Pregnancy
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C502448:NLRP7 protein, human