Disturbed genomic imprinting and its relevance for human reproduction: causes and clinical consequences

Abstract

BACKGROUND Human reproductive issues affecting fetal and maternal health are caused by numerous exogenous and endogenous factors, of which the latter undoubtedly include genetic changes. Pathogenic variants in either maternal or offspring DNA are associated with effects on the offspring including clinical disorders and nonviable outcomes. Conversely, both fetal and maternal factors can affect maternal health during pregnancy. Recently, it has become evident that mammalian reproduction is influenced by genomic imprinting, an epigenetic phenomenon that regulates the expression of genes according to their parent from whom they are inherited. About 1% of human genes are normally expressed from only the maternally or paternally inherited gene copy. Since numerous imprinted genes are involved in (embryonic) growth and development, disturbance of their balanced expression can adversely affect these processes. OBJECTIVE AND RATIONALE This review summarises current our understanding of genomic imprinting in relation to human ontogenesis and pregnancy and its relevance for reproductive medicine. SEARCH METHODS Literature databases (Pubmed, Medline) were thoroughly searched for the role of imprinting in human reproductive failure. In particular, the terms ‘multilocus imprinting disturbances, SCMC, NLRP/NALP, imprinting and reproduction’ were used in various combinations. OUTCOMES A range of molecular changes to specific groups of imprinted genes are associated with imprinting disorders, i.e. syndromes with recognisable clinical features including distinctive prenatal features. Whereas the majority of affected individuals exhibit alterations at single imprinted loci, some have multi-locus imprinting disturbances (MLID) with less predictable clinical features. Imprinting disturbances are also seen in some nonviable pregnancy outcomes, such as (recurrent) hydatidiform moles, which can therefore be regarded as a severe form of imprinting disorders. There is growing evidence that MLID can be caused by variants in the maternal genome altering the imprinting status of the oocyte and the embryo, i.e. maternal effect mutations. Pregnancies of women carrying maternal affect mutations can have different courses, ranging from miscarriages to birth of children with clinical features of various imprinting disorders. WIDER IMPLICATIONS Increasing understanding of imprinting disturbances and their clinical consequences have significant impacts on diagnostics, counselling and management in the context of human reproduction. Defining criteria for identifying pregnancies complicated by imprinting disorders facilitates early diagnosis and personalised management of both the mother and offspring. Identifying the molecular lesions underlying imprinting disturbances (e.g. maternal effect mutations) allows targeted counselling of the family and focused medical care in further pregnancies.

Loss-of-function maternal-effect mutations of PADI6 are associated with familial and sporadic Beckwith-Wiedemann syndrome with multi-locus imprinting disturbance

“…Recently, a number of maternal-effect variants mostly affecting the components of the oocyte SCMC have been associated with MLID. However, the presence of heterogeneous phenotypes in the offspring of the carrier mothers makes prediction of the clinical condition and determination of recurrence risks very challenging [ 7 ]. Several studies have indicated PADI6 variants as the cause of female infertility [ 16 – 19 ], but its role in imprinting disorders is less well established [ 20 ].…”

“…Most of the maternal-effect genes associated with MLID or hydatidiform mole encode for components of the subcortical maternal complex (SCMC) that is localized in the periphery of the oocyte cytoplasm and early embryo until the blastocyst stage [9]. Among these genes, more compelling pieces of evidence have been provided for association of NLRP2, NLRP5, NLRP7, and KHDC3L, while the role of PADI6, OOEP, and TLE6 in the etiology of imprinting disorders is not definitely established [7]. Although several important functions have been attributed to the SCMC during oocyte-to-embryo transition and early development (for a review, see [9]), the mechanisms through which this protein complex influences methylation imprinting remain elusive.…”

“…[ 4 ]) in BWS with KCNQ1OT1 :TSS-DMR LOM [ 5 , 6 ]. Its etiology is unknown in the majority of the cases [ 7 ]. However, in a number of families, causative loss-of-function mutations affecting either zygotic or oocyte-derived trans -acting factors have been found in the patients with MLID or in their mothers, respectively [ 1 ].…”

“…However, in a number of families, causative loss-of-function mutations affecting either zygotic or oocyte-derived trans -acting factors have been found in the patients with MLID or in their mothers, respectively [ 1 ]. In particular, zygotic mutations affecting the zinc-finger ZFP57 gene have been identified in the transient neonatal diabetes type 1 (TNDM1) [ 8 ], while maternal-effect mutations have been reported in healthy women with offspring with MLID and variable imprinting disorders including BWS, or women with reproductive problems, such as infertility, recurrent pregnancy loss, or hydatidiform mole [ 7 ]. Maternal-effect genes are abundantly expressed in oocytes but exert their phenotypic effect in the offspring, being critical for correct development of early embryos.…”

Double sperm cloning (DSC) is a promising strategy in mammalian genetic engineering and stem cell research

“…Genomic imprinting occurs via an epigenetic mechanism, which means that some imprinted genes are only expressed from their maternal allele, while others are only expressed from their paternal allele. Approximately 1% of human genes are normally expressed from only the maternally or paternally inherited gene copy [129]. Mammals are biparental diploid organisms, and both maternal and paternal genomes are required for normal development.…”