Novel single-nucleotide polymorphisms of LHX8 gene in Korean women with premature ovarian insufficiency

Jeon, Sanghyun; Won, Hyung Jae; Kim, You Shin; Lyu, Sang Woo; Seok, Hyun; Kim, Nam Keun; Lee, Woo Sik; Shim, Sung Han; Yoon, Tae Ki; Choi, Youngsok

doi:10.1007/s13258-010-0008-7

Cited by 3 publications

(4 citation statements)

References 17 publications

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“…For example, germ cell cyst breakdown, primordial follicle assembly, and follicle maturation are superficially comparable and many-though not all-genes regulating these processes are orthologous. Studies conducted on Caucasian and Korean populations did not find LHX8 variants associated with premature ovarian insufficiency, in which menopause occurs before age 40 [67,68], but the contribution of LHX8 to fertility and premature menopause beyond 40 years of age has yet to be assessed.…”

Section: Dna Damage and Autophagymentioning

confidence: 99%

Lhx8 ablation leads to massive autophagy of mouse oocytes associated with DNA damage†

D'Ignazio

Michel

Beyer

et al. 2018

Biology of Reproduction

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Following proliferation of oogonia in mammals, great numbers of germ cells are discarded, primarily by apoptosis, while the remainder form primordial follicles (the ovarian reserve) that determine fertility and reproductive lifespan. More massive, rapid, and essentially total loss of oocytes, however, occurs when the transcription factor Lhx8 is ablated-though the cause and mechanism of germ cell loss from the Lhx8-/-ovaries has been unknown. We found that Lhx8−/− ovaries maintain the same number of germ cells throughout embryonic development; rapid decrease in the pool of oocytes starts shortly before birth. The loss results from activation of autophagy, which becomes overwhelming within the first postnatal week, with extracellular matrix proteins filling the space previously occupied by follicles to produce a fibrotic ovary. Associated with this process, as early as a few days before birth, Lhx8-/-oocytes failed to repair DNA damage-which normally occurs when meiosis is initiated during embryonic development; and DNA damage repair genes were downregulated throughout the oocyte short lifespan. Based on gene expression analyses and morphological changes, we propose a model in which lineage-restricted failure of DNA repair triggers germ cell autophagy, causing premature depletion of the ovarian reserve in Lhx8-/-mice. Summary SentenceAblation of Lhx8 causes premature loss of germ cells by autophagy associated with impairment of DNA damage repair during meiosis.

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Section: Dna Damage and Autophagymentioning

confidence: 99%

Lhx8 ablation leads to massive autophagy of mouse oocytes associated with DNA damage†

D'Ignazio

Michel

Beyer

et al. 2018

Biology of Reproduction

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“…Thus, Lhx8 may be a key fertility mediator in humans and a candidate gene for premature ovarian failure (85). However, mutations in Lhx8 exons are uncommon in Caucasians and Koreans with premature ovarian failure (86, 87).…”

Section: Lhx6 and ‐8 In Other Systemsmentioning

confidence: 99%

Lhx6 and Lhx8: cell fate regulators and beyond

et al. 2015

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As transcription factors of the lines (LIN)-11/Islet (Isl)-1/mitosis entry checkpoint (MEC)-3 (LIM)-homeobox subfamily, LIM homeobox (Lhx)6 and -8 are remarkably conserved and involved in the morphogenesis of multiple organ systems. Lhx6 and -8 play overlapping and distinctive roles, but in general act as cell fate mediators and in turn are regulated by several transcriptional factors, such as sonic hedgehog, fibroblast growth factors, and wingless-int (Wnt)/b-catenin. In this review, we first summarize Lhx6 and -8 distributions in development and then explore how Lhx6 and -8 act as transcription factors and coregulators of cell lineage specification. Known Lhx6 and -8 functions and targets are outlined in neurogenesis, craniofacial development, and germ cell differentiation. The underlying mechanisms of Lhx6 and -8 in regulating cell fate remain elusive. Whether Lhx6 and -8 affect functions in tissues and organs other than neural, craniofacial, oocytes, and germ cells is largely unexplored. Taken together, Lhx6 and -8 are important regulators of cell lineage specification and may act as one of the pivotal mediators of stem cell fate. Undoubtedly, future investigations of Lhx6 and -8 biology will continue to yield fascinating insights into tissue development and homeostasis, in addition to their putative roles in tissue regeneration and ageing.-Zhou, C., Yang, G., Chen, M., He, L., Xiang, L., Ricupero, C., Mao, J. J., Ling, J. Lhx6 and Lhx8: cell fate regulators and beyond. FASEB J. 29, 4083-4091 (2015). www.fasebj.org

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“…In another study, 96 women with POF from a Korean population were screened. Sequence analysis revealed 4 known SNPs, 2 novel SNPs in intron 4 (c.114+99C>A), (c.114+100C>A) and 1 in intron 6 (c.390+77C>G) were identified [Jeon et al, 2010]. However, these variants are polymorphic as they are present at almost identical frequencies in control women and therefore unlikely to be causative of POF [Qin et al, 2008;Jeon et al, 2010;Zhou et al, 2015].…”

Section: Lim-hd Genes In Disorders Of Sex Developmentmentioning

confidence: 99%

“…Sequence analysis revealed 4 known SNPs, 2 novel SNPs in intron 4 (c.114+99C>A), (c.114+100C>A) and 1 in intron 6 (c.390+77C>G) were identified [Jeon et al, 2010]. However, these variants are polymorphic as they are present at almost identical frequencies in control women and therefore unlikely to be causative of POF [Qin et al, 2008;Jeon et al, 2010;Zhou et al, 2015]. No other studies have investigated the LHX8 gene in the context of POF or other germ cell-related abnormalities in humans.…”

Section: Lim-hd Genes In Disorders Of Sex Developmentmentioning

confidence: 99%

LIM Homeodomain (LIM-HD) Genes and Their Co-Regulators in Developing Reproductive System and Disorders of Sex Development

Singh¹,

Singh²,

Modi³

2021

Sex Dev

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LIM homeodomain (LIM-HD) family genes are transcription factors that play crucial roles in a variety of functions during embryonic development. The activities of the LIM-HD proteins are regulated by the co-regulators LIM only (LMO) and LIM domain-binding (LDB). In the mouse genome, there are 13 LIM-HD genes (Lhx1–Lhx9, Isl1–2, Lmx1a–1b), 4 Lmo genes (Lmo1–4), and 2 Ldb genes (Ldb1–2). Amongst these, Lhx1 is required for the development of the müllerian duct epithelium and the timing of the primordial germ cell migration. Lhx8 is necessary for oocyte differentiation and Lhx9 for somatic cell proliferation in the genital ridges and control of testosterone production in the Leydig cells. Lmo4 is involved in Sertoli cell differentiation. Mutations in LHX1 are associated with müllerian agenesis or Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome. LHX9 gene variants are reported in cases with disorders of sex development (DSD). Mutations in LHX3 and LHX4 are reported in patients with combined pituitary hormone deficiency having absent or delayed puberty. A transcript map of the Lhx, Lmo, and Ldb genes reveal that multiple LIM-HD genes and their co-regulators are expressed in a sexually dimorphic pattern in the developing mouse gonads. Unraveling the roles of LIM-HD genes during development will aid in our understanding of the causes of DSD.

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Novel single-nucleotide polymorphisms of LHX8 gene in Korean women with premature ovarian insufficiency

Cited by 3 publications

References 17 publications

Lhx8 ablation leads to massive autophagy of mouse oocytes associated with DNA damage†

Lhx8 ablation leads to massive autophagy of mouse oocytes associated with DNA damage†

Lhx6 and Lhx8: cell fate regulators and beyond

LIM Homeodomain (LIM-HD) Genes and Their Co-Regulators in Developing Reproductive System and Disorders of Sex Development

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