Genome-wide copy number analysis and systematic mutation screening in 58 patients with hypogonadotropic hypogonadism

Izumi, Yasukatsu; Suzuki, Erina; Kanzaki, Sho; Yatsuga, Shuichi; Kinjo, Saori; Igarashi, Maki; Maruyama, Tetsuo; Shinzaki, Shinichiro; Horikawa, Reiko; Sato, Naoko; Nakabayashi, Kazuhiko; Hata, Kenichiro; Umezawa, Akihiro; Ogata, Tsutomu; Yoshimura, Yasunori; Fukami, Maki

doi:10.1016/j.fertnstert.2014.06.017

Cited by 38 publications

(38 citation statements)

References 34 publications

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“…Sequence data were analyzed as described previously [Katoh-Fukui et al, 2015]. In this study, we focused on 32 genes known to be involved in the regulation of the HPG axis [Izumi et al, 2014;Macedo et al, 2016]. Possible pathogenic mutations were confirmed by Sanger sequencing.…”

Section: Molecular Analysismentioning

confidence: 99%

NR0B1 Frameshift Mutation in a Boy with Idiopathic Central Precocious Puberty

Shima¹,

Yatsuga

Nakamura³

et al. 2016

Sex Dev

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NR0B1 is the causative gene for X-linked adrenal hypoplasia congenita, characterized by adrenal insufficiency, hypogonadotropic hypogonadism, and infertility. We identified an NR0B1 frameshift mutation in a boy with precocious puberty who had no signs of adrenal insufficiency. Blood examination revealed elevated testosterone levels and gonadotropin hyperresponses to gonadotropin releasing hormone (GnRH) stimulation, together with normal adrenal hormone levels. GnRH analog treatment partially ameliorated his clinical features. Molecular analysis identified a p.Glu3fsAla*16 in NR0B1. These results expand the clinical manifestations of NR0B1 mutations to include central precocious puberty without adrenal insufficiency. NR0B1 mutations likely underlie androgen overproduction via GnRH-dependent and -independent mechanisms.

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Section: Molecular Analysismentioning

confidence: 99%

NR0B1 Frameshift Mutation in a Boy with Idiopathic Central Precocious Puberty

Shima¹,

Yatsuga

Nakamura³

et al. 2016

Sex Dev

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“…Disruption of the WDR11 gene has been found in both human glioma cells (34) and breast cancer cells (36), leading to the suggestion that WDR11 may act as a tumor suppressor, and mutations in WDR11 have also been reported in patients with idiopathic hypogonadotropic hypogonadism (IHH), Kallmann syndrome (KS), and combined pituitary hormone deficiency (CPHD) (37), conditions characterized by low sex steroids and delayed puberty (35,38). Additionally, depletion of WDR11 was found to sensitize cells to the ABtype toxin ricin (39).…”

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confidence: 99%

Cellular Protein WDR11 Interacts with Specific Herpes Simplex Virus Proteins at thetrans-Golgi Network To Promote Virus Replication

Taylor

Mossman

2015

J Virol

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It has recently been proposed that the herpes simplex virus (HSV) protein ICP0 has cytoplasmic roles in blocking antiviral signaling and in promoting viral replication in addition to its well-known proteasome-dependent functions in the nucleus. However, the mechanisms through which it produces these effects remain unclear. While investigating this further, we identified a novel cytoplasmic interaction between ICP0 and the poorly characterized cellular protein WDR11. During an HSV infection, WDR11 undergoes a dramatic change in localization at late times in the viral replication cycle, moving from defined perinuclear structures to a dispersed cytoplasmic distribution. While this relocation was not observed during infection with viruses other than HSV-1 and correlated with efficient HSV-1 replication, the redistribution was found to occur independently of ICP0 expression, instead requiring viral late gene expression. We demonstrate for the first time that WDR11 is localized to the transGolgi network (TGN), where it interacts specifically with some, but not all, HSV virion components, in addition to ICP0. Knockdown of WDR11 in cultured human cells resulted in a modest but consistent decrease in yields of both wild-type and ICP0-null viruses, in the supernatant and cell-associated fractions, without affecting viral gene expression. Although further study is required, we propose that WDR11 participates in viral assembly and/or secondary envelopment. IMPORTANCEWhile the TGN has been proposed to be the major site of HSV-1 secondary envelopment, this process is incompletely understood, and in particular, the role of cellular TGN components in this pathway is unknown. Additionally, little is known about the cellular functions of WDR11, although the disruption of this protein has been implicated in multiple human diseases. Therefore, our finding that WDR11 is a TGN-resident protein that interacts with specific viral proteins to enhance viral yields improves both our understanding of basic cellular biology as well as how this protein is co-opted by HSV. W ith worldwide seroprevalence rates reaching 60 to 90% (1), herpes simplex virus 1 (HSV-1) is a tremendously successful human pathogen. HSV-1 particles consist of a double-stranded DNA genome encased by an icosahedral capsid, surrounded by a proteinaceous layer known as the tegument, which is in turn enclosed by an envelope of host-derived lipids (2). During the lytic replication cycle, viral glycoprotein-mediated fusion of the envelope with the host cell plasma membrane releases the capsid and tegument proteins into the cytosol (3). HSV capsids are then transported to the nucleus along microtubules via molecular motor proteins (4). The release of the genome into the nucleus is followed by viral gene expression in a sequential manner, beginning with the immediate-early (IE) genes and then progressing to the early (E) and late (L) classes, resulting in viral genomic DNA replication and packaging into capsids.Although subsequent steps have been controversial, it is n...

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“…This method is particularly useful to elucidate the genetic causes of Mendelian disorders with multiple causative genes. In our recent studies13141516), we performed NGS analyses for several samples of patients with pediatric endocrine disorders (Fig. 1).…”

Section: Molecular Diagnosis Of Pediatric Endocrine Disorders Using Ngsmentioning

confidence: 99%

“…1). For example, we investigated the genetic causes of hypogonadotropic hypogonadism (HH), a rare condition caused by monoallelic, biallelic, or oligogenic mutations in more than 20 genes1316). We created a custom-made NGS panel that covers most known causative genes for HH.…”

Section: Molecular Diagnosis Of Pediatric Endocrine Disorders Using Ngsmentioning

confidence: 99%

Next generation sequencing and array-based comparative genomic hybridization for molecular diagnosis of pediatric endocrine disorders

Fukami

Miyado

2017

Ann Pediatr Endocrinol Metab

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Next-generation sequencing (NGS) and array-based comparative genomic hybridization (array CGH) have enabled us to perform high-throughput mutation screening and genome-wide copy number analysis, respectively. These methods can be used for molecular diagnosis of pediatric endocrine disorders. NGS has determined the frequency and phenotypic variation of mutations in several disease-associated genes. Furthermore, whole exome analysis using NGS has successfully identified several novel causative genes for endocrine disorders. Array CGH is currently used as the standard procedure for molecular cytogenetic analysis. Array CGH can detect various submicroscopic genomic rearrangements involving exons or enhancers of disease-associated genes. This review introduces some examples of the use of NGS and array CGH for the molecular diagnosis of pediatric endocrine disorders.

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Genome-wide copy number analysis and systematic mutation screening in 58 patients with hypogonadotropic hypogonadism

Cited by 38 publications

References 34 publications

<b><i>NR0B1</i></b> Frameshift Mutation in a Boy with Idiopathic Central Precocious Puberty

<b><i>NR0B1</i></b> Frameshift Mutation in a Boy with Idiopathic Central Precocious Puberty

Cellular Protein WDR11 Interacts with Specific Herpes Simplex Virus Proteins at thetrans-Golgi Network To Promote Virus Replication

Next generation sequencing and array-based comparative genomic hybridization for molecular diagnosis of pediatric endocrine disorders

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