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Eur J Hum Genet. 2016 Oct;24(10):1445-52. doi: 10.1038/ejhg.2016.9. Epub 2016 Mar 9.

The genomic architecture of NLRP7 is Alu rich and predisposes to disease-associated large deletions.

Author information

1
Department of Human Genetics, McGill University Health Centre Research Institute, Montréal, Canada.
2
Department of Obstetrics and Gynaecology, McGill University Health Centre Research Institute, Montréal, Canada.
3
Laboratoire de Génétique des Maladies Rares et Autoinflammatoires, Hôpital Arnaud de Villeneuve, Montpellier, France.
4
Genetics Department, Shiraz University of Medical Sciences, Shiraz, Iran.
5
Hospital Aranda de la Parra, Laboratorio-sótano, Hidalgo, Centro Leon Gto, Mexico.
6
Ege University Medical Faculty, Department of Medical Genetics, Izmir, Turkey.
7
Genetiks Genetic Laboratory, Istanbul, Turkey.
8
Kuwait Medical Genetic Center, Kuwait Pediatric Department, Kuwait City, Kuwait.
9
Division of Maternal-Fetal Medicine, Comprehensive Hemostasis & Thrombosis Center, Duke University Medical Centre, Durham, NC, USA.
10
Institut Ste Catherine, Avignon, France.
11
Gynecologic and Obstetrics, Department University Hospital Amiens, Amiens, France.
12
Medical Genetics Department, Sarem Fertility & Infertility Research Center (SAFIR), Tehran, Iran.
13
Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, The University of North Carolina, Chapel Hill, USA.
14
Department of Obstetrics and Gynaecology, Oncology Unit, Kanuni Sultan Suleyman Training and Research Hospital, Istanbul, Turkey.

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.

PMID:
26956250
PMCID:
PMC5027696
DOI:
10.1038/ejhg.2016.9
[Indexed for MEDLINE]
Free PMC Article

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