The ancestral gene for transcribed, low-copy repeats in the Prader- Willi/Angelman region encodes a large protein implicated in protein trafficking, which is deficient in mice with neuromuscular and spermiogenic abnormalities

Ji, Yuandong; Walkowicz, Mitchell J.; Buiting, Karin; Johnson, Dabney K.; Tarvin, Rocio; Rinchik, Eugene M.; Horsthemke, Bernhard; Stubbs, Lisa; Nicholls, Robert D.

doi:10.1093/hmg/8.3.533

Cited by 105 publications

(123 citation statements)

References 41 publications

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“…These duplicons contain at least seven different expressed sequences and are thought to have been generated approximately 20 million years ago. One of the duplicon-containing expressed sequences is the HERC2 gene (HEct domain and RCc1 domain protein 2; also known as ERY-1), 13 which has been found rearranged at the mRNA level in a PWS patient. 10 Around 11 HERC2 copies have been identified in chromosomes 15 and 16, but most of them are on 15q11-q13.…”

Section: Introductionmentioning

confidence: 99%

Human chromosome 15q11-q14 regions of rearrangements contain clusters of LCR15 duplicons

et al. 2002

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Six breakpoint regions for rearrangements of human chromosome 15q11-q14 have been described. These rearrangements involve deletions found in approximately 70% of Prader-Willi or Angelman's syndrome patients (PWS, AS), duplications detected in some cases of autism, triplications and inverted duplications. HERC2-containing (HEct domain and RCc1 domain protein 2) segmental duplications or duplicons are present at two of these breakpoints (BP2 and BP3) mainly associated with deletions. We show here that clusters containing several copies of the human chromosome 15 low-copy repeat (LCR15) duplicon are located at each of the six described 15q11-q14 BPs. In addition, our results suggest the existence of breakpoints for large 15q11-q13 deletions in a proximal duplicon-containing clone. The study reveals that HERC2-containing duplicons (estimated on 50 ± 400 kb) and LCR15 duplicons (*15 kb on 15q11-q14) share the golgin-like protein (GLP) genomic sequence. Through the analysis of a human BAC library and public databases we have identified 36 LCR15 related sequences in the human genome, most (27) mapping to chromosome 15q and being transcribed. LCR15 analysis in non-human primates and age-sequence divergences support a recent origin of this family of segmental duplications through human speciation.

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Section: Introductionmentioning

confidence: 99%

Human chromosome 15q11-q14 regions of rearrangements contain clusters of LCR15 duplicons

et al. 2002

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“…By contrast, the murine HERC1 gene is ubiquitously expressed and a variety of mutations have been reported in several members of the HERC families, leading to sterility, growth retardation, retinitis pigmentosa, amyotrophic lateral sclerosis or cancer. 13,14 Notably, the tambaleante (tbl) mutant mice is caused by a homozygous missense mutation (p.Gly483Glu) in HERC1, resulting in progressive Purkinje cell degeneration, severe ataxia and growth retardation. 15 In contrast to what is observed in our patient, the Herc1 tbl mutation enhances the stability of the Herc1 protein.…”

Section: Discussionmentioning

confidence: 99%

A nonsense variant in HERC1 is associated with intellectual disability, megalencephaly, thick corpus callosum and cerebellar atrophy

et al. 2015

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Megalencephaly is a congenital condition characterized by severe overdeveloped brain size. This phenotype is often caused by mutations affecting the RTK/PI3K/mTOR (receptor tyrosine kinase-phosphatidylinositol-3-kinase-AKT) signaling and its downstream pathway of mammalian target of rapamycin (mTOR). Here, using a whole-exome sequencing in a Moroccan consanguineous family, we show that a novel autosomal-recessive neurological condition characterized by megalencephaly, thick corpus callosum and severe intellectual disability is caused by a homozygous nonsense variant in the HERC1 gene. Assessment of the primary skin fibroblast from the proband revealed complete absence of the HERC1 protein. HERC1 is an ubiquitin ligase that interacts with tuberous sclerosis complex 2, an upstream negative regulator of the mTOR pathway. Our data further emphasize the role of the mTOR pathway in the regulation of brain development and the power of next-generation sequencing technique in elucidating the genetic etiology of autosomal-recessive disorders and suggest that HERC1 defect might be a novel cause of autosomal-recessive syndromic megalencephaly. European Journal of Human Genetics (2016) 24, 455-458; doi:10.1038/ejhg.2015.140; published online 8 July 2015 INTRODUCTIONMegalencephaly is defined as an oversized and overweight brain that exceeds the age-related mean by 2 or more standard deviations and is often associated with other growth anomalies and severe intellectual disability (ID). 1 Disruptions of various stages of brain development, neuronal growth, proliferation and/or migration are believed to be the underlying causes of the malformation. 2 The PI3K/AKT/mTOR (phosphatidylinositol-3-kinase/AKT/mammalian target of rapamycin) pathway controls key cellular responses such as cell growth and proliferation, survival, migration and metabolism; mutations in various core members and upstream regulators of this pathway are responsible for a large proportion of megalencephaly-related disorders. 2 De novo mutations in PIK3CA, AKT3 and MTOR are found in 30% of cases of hemimegalencephaly, 3 whereas de novo and postzygotic mutations in AKT3, PIK3R2, PIK3CA and CCND2 cause 74% of cases of megalencephaly-capillary malformation and megalencephaly-polymicrogyria-polydactyly-hydrocephalus. 4,5 Moreover, mutations in other components of mTOR could manifest neurological symptoms without megalencephaly, such as ID, autism or epilepsy, as seen in patients with mutations in TSC1 (tuberous sclerosis complex 2), TSC2, PINK1 and DISC1. 6 These findings strongly support the role of the mTOR pathway in the development and function of the brain. In this study, we provide evidence linking mutation in HERC1, another regulator of the mTOR pathway, to a distinct form of megalencephaly.

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“…Although several sensitive and specific genes for predicting lung cancer risk had been found (Begum et al, 2011), biomarkers with the ability to distinguish benign from malignant lesions were still unable to meet our demand. Last several years, increasing evidence had showed the important role of ubiquitin-proteasome system in tumorigenesis (Ji et al, 1999;Deng and Scott, 2000), which drew our strong attention. HERC4 was recently identified to be a member of HERC family and it had some association with ubiquitin ligase.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, there are conflicting reports about decreased proteasome activity suspected to play a key role in conformational diseases such as Parkinson's and Huntington's disease (Lindsten and Dantuma, 2003). Researchers are telling us in various aspects that the links between members of the UPS and carcinogenesis (Ji et al, 1999;Deng and Scott, 2000). Consequently, the role of the UPS in its regulation has become an area of intense interest.…”

Section: Expression Of Herc4 In Lung Cancer and Its Correlation With mentioning

confidence: 99%

“…On the one hand, RLD could function as guanine nucleotide exchange factor (GEF) for Ran like RCC1, which participates in nucleocytoplasmic transport and mitotic spindle formation. On the other hand, the HECT domain was firstly defined in E6-AP-mediated ubiquitination of p53 and performs as ubiquitin ligase (Ji et al, 1999). HERC4 was located in chromosome 10q22, composing of 26 exons.…”

Section: Expression Of Herc4 In Lung Cancer and Its Correlation With mentioning

confidence: 99%

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Expression of HERC4 in Lung Cancer and its Correlation with Clinicopathological Parameters

Zeng

Chen²,

Zhou³

et al. 2015

Asian Pacific Journal of Cancer Prevention

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Asian Pac J Cancer Prev, 16 (2), 513-517 IntroductionLung cancer is the leading cause of death of cancer world-wide, causing more than 1 million deaths per year (Jemal et al., 2010). It is a disease characterized by uncontrolled cell growth in tissues of the lung. The global cancer burden in annual cases is projected to double by 2050, and lung cancer is expected to remain the leading cause of all cancer deaths during that time (Brothers et al., 2013). Cigarette smoking remains the main risk factor for lung cancer, with 85%-90% percent of lung cancer cases caused by active or passive smoking. Conventional treatments for lung cancer are surgery, radiotherapy and chemotherapy. And the choice of method depends on the type, progress and relevant genes of lung cancer. Besides, targeted therapy, as a more accurate and specific treatment, has come into our field of vision for us to choose from. It won't cause any harm to adjacent normal lung cells when it uses specific drugs to identify and target cancer cells.Recently, genetic, transcriptomic and epigenomic biomarkers are emerging as tools for the early diagnosis of lung cancer both in the screening setting and diagnostic. Furthermore, epigenetics refers to heritable modifications

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The ancestral gene for transcribed, low-copy repeats in the Prader- Willi/Angelman region encodes a large protein implicated in protein trafficking, which is deficient in mice with neuromuscular and spermiogenic abnormalities

Cited by 105 publications

References 41 publications

Human chromosome 15q11-q14 regions of rearrangements contain clusters of LCR15 duplicons

Human chromosome 15q11-q14 regions of rearrangements contain clusters of LCR15 duplicons

A nonsense variant in HERC1 is associated with intellectual disability, megalencephaly, thick corpus callosum and cerebellar atrophy

Expression of HERC4 in Lung Cancer and its Correlation with Clinicopathological Parameters

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