TY - JOUR
T1 - Report of four new patients with protein-truncating mutations in C6orf221/KHDC3L and colocalization with NLRP7
AU - Reddy, Ramesh
AU - Akoury, Elie
AU - Phuong Nguyen, Ngoc Minh
AU - Abdul-Rahman, Omar A.
AU - Dery, Christine
AU - Gupta, Neerja
AU - Daley, William P.
AU - Ao, Asangla
AU - Landolsi, Hanene
AU - Ann Fisher, Rosemary
AU - Touitou, Isabelle
AU - Slim, Rima
PY - 2013/9/1
Y1 - 2013/9/1
N2 - 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.
AB - 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.
KW - 4-bp deletion
KW - colocalization
KW - diploid biparental hydatidiform mole
KW - KHDC3L
KW - NLRP7
UR - http://www.scopus.com/inward/record.url?scp=84882451126&partnerID=8YFLogxK
U2 - 10.1038/ejhg.2012.274
DO - 10.1038/ejhg.2012.274
M3 - Article
C2 - 23232697
AN - SCOPUS:84882451126
SN - 1018-4813
VL - 21
SP - 957
EP - 964
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 9
ER -