Mutations Causing Familial Biparental Hydatidiform Mole Implicate C6orf221 as a Possible Regulator of Genomic Imprinting in the Human Oocyte

Parry, David; Logan, Clare V.; Hayward, Bruce E.; Shires, Michael; Landolsi, Hanène; Diggle, Christine P.; Carr, Ian; Rittore, Cécile; Touitou, Isabelle; Philibert, Laurent; Fisher, Rosemary A.; Fallahian, Masoumeh; Huntriss, John; Picton, Helen M.; Malik, Sabreena; Taylor, Graham R.; Johnson, Colin A.; Bonthron, David T.; Sheridan, Eamonn

doi:10.1016/j.ajhg.2011.08.002

Cited by 211 publications

(171 citation statements)

References 45 publications

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“…This is a pure maternal-effect recessive inherited disorder attributable to mutations of NLRP7 or C6orf221, resulting in a multi-locus epigenetic defect with failure to establish maternal identity at imprinted loci and abnormal expression of imprinted genes. [53][54][55][56][57][58][59][60][61] Patients with this disorder can have multiple/recurrent complete hydatidiform moles that are morphologically, immunophenotypically, and clinically similar to conventional complete hydatidiform moles, that is, they are p57-negative and appear to have a similar risk of persistent gestational Only two cases in our study had the combination of a p57-negative result and biparental diploidy; these did not have any morphology features to suggest a complete hydatidiform mole. Another case with a negative p57 result and unsatisfactory genotyping was quite immature and also lacked any diagnostic features of a complete hydatidiform mole.…”

Section: Discussionmentioning

confidence: 55%

Characteristics of hydatidiform moles: analysis of a prospective series with p57 immunohistochemistry and molecular genotyping

et al. 2014

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Immunohistochemical analysis of cyclin-dependent kinase inhibitor 1C (CDKN1C, p57, Kip2) expression and molecular genotyping accurately classify hydatidiform moles into complete and partial types and distinguish these from non-molar specimens. Characteristics of a prospective series of all potentially molar specimens encountered in a large gynecologic pathology practice are summarized. Initially, all specimens were subjected to both analyses; this was later modified to triage cases for genotyping based on p57 results: p57-negative cases diagnosed as complete hydatidiform moles without genotyping; all p57-positive cases genotyped. Of the 678 cases, 645 were definitively classified as complete hydatidiform mole (201), partial hydatidiform mole (158), non-molar (272), and androgenetic/biparental mosaic (14); 33 were unsatisfactory, complex, or problematic. Of the 201 complete hydatidiform moles, 104 were p57-negative androgenetic and an additional 95 were p57-negative (no genotyping), 1 was p57-positive (retained maternal chromosome 11) androgenetic, and 1 was p57-non-reactive androgenetic; 90 (85%) of the 106 genotyped complete hydatidiform moles were monospermic and 16 were dispermic. Of the 158 partial hydatidiform moles, 155 were diandric triploid, with 154 p57-positive, 1 p57-negative (loss of maternal chromosome 11), and 1 p57-non-reactive; 3 were triandric tetraploid, with 2 p57-positive and 1 p57-negative (loss of maternal chromosome 11). Of 155 diandric triploid partial hydatidiform moles, 153 (99%) were dispermic and 2 were monospermic. Of the 272 non-molar specimens, 259 were p57-positive biparental diploid, 5 were p57-positive digynic triploid, 2 were p57-negative biparental diploid (no morphological features of biparental hydatidiform mole), and 6 were p57-non-reactive biparental diploid. Of the 14 androgenetic/biparental mosaics with discordant p57 expression, 6 were uniformly mosaic and 8 had a p57-negative androgenetic molar component. p57 expression is highly correlated with genotyping, serves as a reliable marker for diagnosis of complete hydatidiform moles, and identifies androgenetic cell lines in mosaic conceptions. Cases with aberrant and discordant p57 expression can be correctly classified by genotyping.

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Section: Discussionmentioning

confidence: 55%

Characteristics of hydatidiform moles: analysis of a prospective series with p57 immunohistochemistry and molecular genotyping

et al. 2014

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“…15 Recently, mutations in a second maternal-effect gene, KHDC3L, were shown to be responsible for RHMs. 17 Mutations in this gene were found in 1 familial case and in 2 out of 14 analyzed singleton cases of RHMs (14.2%) that are negative for NLRP7 mutations by conventional Sanger sequencing. 17 Among the identified KHDC3L mutations, a 4-bp deletion in exon 2, c.322_325delGACT, p.Asp108Ilefs*30, which was found in a homozygous and heterozygous state in one Tunisian and one Iranian patient, respectively.…”

Section: Introductionmentioning

confidence: 99%

“…17 Mutations in this gene were found in 1 familial case and in 2 out of 14 analyzed singleton cases of RHMs (14.2%) that are negative for NLRP7 mutations by conventional Sanger sequencing. 17 Among the identified KHDC3L mutations, a 4-bp deletion in exon 2, c.322_325delGACT, p.Asp108Ilefs*30, which was found in a homozygous and heterozygous state in one Tunisian and one Iranian patient, respectively. 17 Here, we report two KHDC3L mutations, including one novel 4-bp deletion, in two new singleton cases and one familial case of RHMs.…”

Section: Introductionmentioning

confidence: 99%

“…17 Among the identified KHDC3L mutations, a 4-bp deletion in exon 2, c.322_325delGACT, p.Asp108Ilefs*30, which was found in a homozygous and heterozygous state in one Tunisian and one Iranian patient, respectively. 17 Here, we report two KHDC3L mutations, including one novel 4-bp deletion, in two new singleton cases and one familial case of RHMs. We confirm the causality of KHDC3L mutations in 10% of our patients with RHMs who are negative for NLRP7 mutations and exclude the causative role of KHDC3L in our cohorts of other forms of reproductive losses.…”

Section: Introductionmentioning

confidence: 99%

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Report of four new patients with protein-truncating mutations in C6orf221/KHDC3L and colocalization with NLRP7

et al. 2012

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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.

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“…Both genes were repeatedly seen to be responsible for recurrent hydatidiform moles (RHMs) [54][55][56][57][58][59][60][61]. Despite being diploid biparental, therefore with a normal biparental contribution to their genomes, RHM tissues lack maternal methylation marks on several maternally imprinted genes.…”

Section: Scmc Involvement In Epigenetic Reprogramming Of Zygotesmentioning

confidence: 99%

The subcortical maternal complex: multiple functions for one biological structure?

Bebbere

Masala

Albertini

et al. 2016

J Assist Reprod Genet

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The subcortical maternal complex (SCMC) is a multiprotein complex uniquely expressed in mammalian oocytes and early embryos, essential for zygote progression beyond the first embryonic cell divisions. Similiar to other factors encoded by maternal effect genes, the physiological role of SCMC remains unclear, although recent evidence has provided important molecular insights into different possible functions. Its potential involvement in human fertility is attracting increasing attention; however, the complete story is far from being told. The present mini review provides an overview of recent findings related to the SCMC and discusses its potential physiological role/s with the aim of inspiring new directions for future research.

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Mutations Causing Familial Biparental Hydatidiform Mole Implicate C6orf221 as a Possible Regulator of Genomic Imprinting in the Human Oocyte

Cited by 211 publications

References 45 publications

Characteristics of hydatidiform moles: analysis of a prospective series with p57 immunohistochemistry and molecular genotyping

Characteristics of hydatidiform moles: analysis of a prospective series with p57 immunohistochemistry and molecular genotyping

Report of four new patients with protein-truncating mutations in C6orf221/KHDC3L and colocalization with NLRP7

The subcortical maternal complex: multiple functions for one biological structure?

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