title: Report of four new patients with protein-truncating mutations in C6orf221/KHDC3L and colocalization with NLRP7.
abstract: To date, two maternal-effect genes have been shown to have causative roles in recurrent hydatidiform moles (RHMs); NLRP7 that is mutated in 48-60% of patients with RHMs and C6orf221 (HUGO-approved nomenclature is now KHDC3L), a recently identified gene, that is mutated in 14% of patients with RHMs who are negative for NLRP7 mutations. We sequenced KHDC3L in 97 patients with RHMs and reproductive loss who are mostly negative for NLRP7 mutations. We identified three unrelated patients, each homozygous for one of the two protein-truncating mutations, a novel 4-bp deletion resulting in a frameshift, c.299_302delTCAA, p.Ile100Argfs*2, and a previously described 4-bp deletion, c.322_325delGACT, p.Asp108Ilefs*30, transmitted on a shared haplotype to three patients from different populations. We show that five HM tissues from one of these patients are diploid and biparental similar to HMs from patients with two defective NLRP7 mutations. Using immunofluorescence, we show that KHDC3L protein displays a juxta perinuclear signal and colocalizes with NLRP7 in lymphoblastoid cell lines from normal subjects. Using cell lines from patients, we demonstrate that the KHDC3L mutations do not change the subcellular localization of the protein in hematopoietic cells. Our data highlight the similarities between the two causative genes for RHMs, KHDC3L and NLRP7, in their subcellular localization, the parental contribution to the HM tissues caused by them, and the presence of several founder mutations and variants in both of them indicating positive selection and adaptation.
authors.affiliation: Department of Human Genetics, McGill University Health Centre, Montreal, Canada.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Reddy
authors.forename: Elie
authors.initials: E
authors.lastname: Akoury
authors.forename: Ngoc Minh
authors.initials: NM
authors.lastname: Phuong Nguyen
authors.forename: Omar A
authors.initials: OA
authors.lastname: Abdul-Rahman
authors.forename: Christine
authors.initials: C
authors.lastname: Dery
authors.forename: Neerja
authors.initials: N
authors.lastname: Gupta
authors.forename: William P
authors.initials: WP
authors.lastname: Daley
authors.forename: Asangla
authors.initials: A
authors.lastname: Ao
authors.forename: Hanene
authors.initials: H
authors.lastname: Landolsi
authors.forename: Rosemary
authors.initials: R
authors.lastname: Ann Fisher
authors.forename: Isabelle
authors.initials: I
authors.lastname: Touitou
authors.forename: Rima
authors.initials: R
authors.lastname: Slim
mesh_terms: D000022:Abortion, Spontaneous / Q000235:genetics; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D001483:Base Sequence; D016022:Case-Control Studies; D002824:Chorionic Villi / Q000473:pathology; D004252:DNA Mutational Analysis; D005260:Female; D016368:Frameshift Mutation; D005787:Gene Frequency; D056726:Genetic Association Studies; D057809:HEK293 Cells; D006239:Haplotypes; D006801:Humans; D006828:Hydatidiform Mole / Q000235:genetics*; D008297:Male; D010375:Pedigree; D011247:Pregnancy; D011256:Pregnancy Outcome; D021381:Protein Transport; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D017384:Sequence Deletion; D014594:Uterine Neoplasms / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C568062:KHDC3L protein, human; C502448:NLRP7 protein, human; D011506:Proteins