Lethal Congenital Contractural Syndrome Type 2 (LCCS2) Is Caused by a Mutation in ERBB3 (Her3), a Modulator of the Phosphatidylinositol-3-Kinase/Akt Pathway

Narkis, Ginat; Ofir, Rivka; Manor, Esther; Landau, Daniella; Elbedour, Khalil; Birk, Ohad S.

doi:10.1086/520770

Cited by 61 publications

(62 citation statements)

References 17 publications

(18 reference statements)

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“…5 RNA was extracted from cultured cells of EBV-transformed lymphoblastoid cell lines using the RNeasy Mini Kit (Qiagen, Petach Tikva, Israel) and cDNA was reverse transcribed by the Verso RT-PCR Kits (TAMAR, Mevaseret Zion, Israel) according to the protocol of the manufacturer. 6 Primer pairs for cDNA and/or exons of genomic DNA (including flanking intron sequences) of eight genes in the putative 1p33-1p32.3 locus were designed based on the known mRNA and genomic sequences using Primer3. Primer sequences and PCR conditions are available on request.…”

Section: Sequence Analysismentioning

confidence: 99%

“…3,5 A single region of homozygosity on chromosome 1p33-1p32.3 was identified, that was common to all affected individuals. Fine mapping 2,6 testing the 18 available DNA samples with polymorphic markers narrowed down the locus to 6.75 cM (7.25 Mb) between D1S2824 and D1S200, with a maximum multipoint LOD score of six calculated using SUPERLINK 4 (data not shown).…”

Section: Linkage Analysismentioning

confidence: 99%

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The desmosterolosis phenotype: spasticity, microcephaly and micrognathia with agenesis of corpus callosum and loss of white matter

et al. 2011

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Desmosterolosis is a rare autosomal recessive disorder of elevated levels of the cholesterol precursor desmosterol in plasma, tissue and cultured cells. With only two sporadic cases described to date with two very different phenotypes, the clinical entity arising from mutations in 24-dehydrocholesterol reductase (DHCR24) has yet to be defined. We now describe consanguineous Bedouin kindred with four surviving affected individuals, all presenting with severe failure to thrive, psychomotor retardation, microcephaly, micrognathia and spasticity with variable degree of hand contractures. Convulsions near birth, nystagmus and strabismus were found in most. Brain MRI demonstrated significant reduction in white matter and near agenesis of corpus callosum in all. Genome-wide linkage analysis and fine mapping defined a 6.75 cM disease-associated locus in chromosome 1 (maximum multipoint LOD score of six), and sequencing of candidate genes within this locus identified in the affected individuals a homozygous missense mutation in DHCR24 leading to dramatically augmented plasma desmosterol levels. We thus establish a clear consistent phenotype of desmosterolosis (MIM 602398).

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Section: Sequence Analysismentioning

confidence: 99%

Section: Linkage Analysismentioning

confidence: 99%

The desmosterolosis phenotype: spasticity, microcephaly and micrognathia with agenesis of corpus callosum and loss of white matter

et al. 2011

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“…285,289,290 ERBB3 also has an essential role in development of the human nervous system: lethal congenital contractural syndrome 2, an autosomal recessive trait associated with atrophy of the anterior horn of the spinal cord, is caused by aberrant splicing of ERBB3. 291 In adult rodent brain Erbb3 mRNA, with prominence mainly in white matter, has an expression pattern different from that of Erbb4. 34,292,293 While Erbb3 mRNA was expressed in the ventral and dorsal spinal cord roots of fetal rats, it was absent from these areas in adults.…”

Section: Hematopoietic Neoplasmsmentioning

confidence: 99%

The ERBB3 receptor in cancer and cancer gene therapy

2008

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ERBB3, a member of the epidermal growth factor receptor (EGFR) family, is unique in that its tyrosine kinase domain is functionally defective. It is activated by neuregulins, by other ERBB and nonERBB receptors as well as by other kinases, and by novel mechanisms. Downstream it interacts prominently with the phosphoinositol 3-kinase/AKT survival/mitogenic pathway, but also with GRB, SHC, SRC, ABL, rasGAP, SYK and the transcription regulator EBP1. There are likely important but poorly understood roles for nuclear localization and for secreted isoforms. Studies of ERBB3 expression in primary cancers and of its mechanistic contributions in cultured cells have implicated it, with varying degrees of certainty, with causation or sustenance of cancers of the breast, ovary, prostate, certain brain cells, retina, melanocytes, colon, pancreas, stomach, oral cavity and lung. Recent results link high ERBB3 activity with escape from therapy targeting other ERBBs in lung and breast cancers. Thus a wide and centrally important role for ERBB3 in cancer is becoming increasingly apparent. Several approaches for targeting ERBB3 in cancers have been tested or proposed. Small inhibitory RNA (siRNA) to ERBB3 or AKT is showing promise as a therapeutic approach to treatment of lung adenocarcinoma.

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“…LCCS2 is caused by mutation of ERBB3 (Narkis et al, 2007b), a member of the ERBB family of receptor tyrosine kinases; LCCS3 is caused by mutation of PIP5K1C (Narkis et al, 2007a), which encodes phosphatidylinositol-4-phosphate 5-kinase, type I, gamma (PIPKIγ); LCCS5 is caused by homozygous Dynamin 2 (DNM2) mutation (Koutsopoulos et al, 2013); while another study linked mutations in CNTNAP1 (encoding contactin associated protein 1) and ADCY6…”

Section: Introductionmentioning

confidence: 99%

Deficiency in the mRNA export mediator Gle1 impairs Schwann cell development in the zebrafish embryo

et al. 2016

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-GLE1 mutations cause lethal congenital contracture syndrome 1 (LCCS1), a severe autosomal recessive fetal motor neuron disease, and more recently have been associated with amyotrophic lateral sclerosis (ALS). The gene encodes a highly conserved protein with an essential role in mRNA export. The mechanism linking Gle1 function to motor neuron degeneration in humans has not been elucidated, but increasing evidence implicates abnormal RNA processing as a key event in the pathogenesis of several motor neuron

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Lethal Congenital Contractural Syndrome Type 2 (LCCS2) Is Caused by a Mutation in ERBB3 (Her3), a Modulator of the Phosphatidylinositol-3-Kinase/Akt Pathway

Cited by 61 publications

References 17 publications

The desmosterolosis phenotype: spasticity, microcephaly and micrognathia with agenesis of corpus callosum and loss of white matter

The desmosterolosis phenotype: spasticity, microcephaly and micrognathia with agenesis of corpus callosum and loss of white matter

The ERBB3 receptor in cancer and cancer gene therapy

Deficiency in the mRNA export mediator Gle1 impairs Schwann cell development in the zebrafish embryo

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