<scp>RBM</scp>28, a protein deficient in <scp>ANE</scp> syndrome, regulates hair follicle growth via miR‐203 and p63

Warshauer, Emily; Samuelov, Liat; Sarig, Ofer; Vodo, Dan; Bindereif, Albrecht; Kanaan, Moien; Gat, Uri; Fuchs-Telem, Dana; Shomron, Noam; Farberov, Luba; Pasmanik‐Chor, Metsada; Nardini, Gil; Winkler, Eyal; Meilik, Benjamin; Petit, Isabelle; Aberdam, Daniel; Paus, Ralf; Sprecher, Eli; Nousbeck, Janna

doi:10.1111/exd.12737

Cited by 17 publications

(13 citation statements)

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“…Skin biopsies of 4 mm were taken from the back arm of patients 1 and 2 after family consent and authorization from the French Committed of Person protection (CPP). Primary KCs were extracted and amplified as described previously 15 . By raising calcium concentration to 1.5 mM at confluency, KCs underwent stratification/ differentiation for 10 days.…”

Section: Cell Culture and Epidermal Differentiationmentioning

confidence: 99%

Improvement of epidermal covering on AEC patients with severe skin erosions by PRIMA-1MET/APR-246

et al. 2020

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P63 is a major transcription factor regulating skin development and homeostasis. It controls many genes involved in cell proliferation, adhesion, and early differentiation. P63 is mutated in several rare syndromes called p63-related ectodermal dysplasia syndromes (ED). The main forms are EEC and AEC syndromes due to p63 missense mutations on the DBD and SAM domains, respectively. ED patients display many developmental defects, including ectrodactyly, clef/ lip palate, and ectodermal dysplasia, while AEC patients suffer from severe skin erosions that not always heal. We have previously showed that ED-derived iPSC display altered epidermal commitment. P63 belongs to the p53 gene family sharing similar structural domains. We found that ED-iPSC epidermal commitment can be rescued by a p53reactivating compounds called PRIMA-1 MET , also named APR-246 and currently used in anticancer clinical trials. Here, we established primary epidermal culture from two AEC children (S.F. and Y.M.) suffering from persistent skin erosions at age of 9 and 15, respectively. These patients carry missense mutations on the SAM domain (I576T and I537T). We found that primary keratinocytes (KCs) isolated from these AEC patients underwent altered epidermal differentiation that was rescued by PRIMA-1 MET treatment. It prompted us to formulate the compound onto a cream that was topically applied on the right hand of one patient and on the scalp of the second patient. In both cases, the daily treatment allowed re-epithelialization of the eroded skin and a drastic loss of pain after few weeks, improving quality of life. Normally, mutant p63 exerts a dominant-negative effect, mainly through the formation of aggregate with WT p63 and p73. PRIMA-1 MET did not reduce protein aggregation while enhancing cell differentiation, suggesting that PRIMA-1 MET targets cell differentiation and not p63 activity directly. In conclusion, we propose that repurposing of the antitumoral PRIMA-1 MET compound could become a general treatment of AEC skin erosions.

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Section: Cell Culture and Epidermal Differentiationmentioning

confidence: 99%

Improvement of epidermal covering on AEC patients with severe skin erosions by PRIMA-1MET/APR-246

et al. 2020

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“…A homozygous missense mutation in the nucleolar protein RBM28 causes the ribosomopathy, alopecia, neurological defects and endocrinopathy (ANE) syndrome ( Nousbeck et al, 2008 ). Five affected children of a consanguineous kindred displayed degrees of baldness, mental retardation, motor deterioration, and reduced pituitary gland function in their second decade of life ( Nousbeck et al, 2008 ; Warshauer et al, 2015 ). The mutation segregated in the family in an autosomal recessive manner and was mapped to a single leucine to proline amino acid substitution at position 351 (L351P) of RBM28.…”

Section: Introductionmentioning

confidence: 99%

The molecular basis for ANE syndrome revealed by the large ribosomal subunit processome interactome

McCann

Teramoto

Zhang

et al. 2016

eLife

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ANE syndrome is a ribosomopathy caused by a mutation in an RNA recognition motif of RBM28, a nucleolar protein conserved to yeast (Nop4). While patients with ANE syndrome have fewer mature ribosomes, it is unclear how this mutation disrupts ribosome assembly. Here we use yeast as a model system and show that the mutation confers growth and pre-rRNA processing defects. Recently, we found that Nop4 is a hub protein in the nucleolar large subunit (LSU) processome interactome. Here we demonstrate that the ANE syndrome mutation disrupts Nop4’s hub function by abrogating several of Nop4’s protein-protein interactions. Circular dichroism and NMR demonstrate that the ANE syndrome mutation in RRM3 of human RBM28 disrupts domain folding. We conclude that the ANE syndrome mutation generates defective protein folding which abrogates protein-protein interactions and causes faulty pre-LSU rRNA processing, thus revealing one aspect of the molecular basis of this human disease.DOI: http://dx.doi.org/10.7554/eLife.16381.001

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“…Nevertheless, the expression pattern also shows variability in level of expression, suggesting a tissue-specific role. Indeed, human RBM28 deficiency is not lethal and shows some specific phenotypes including alopecia, mental retardation, progressive motor decline, and hypopituitarism (ANE syndrome) [ 35 , 36 ].…”

Section: Discussionmentioning

confidence: 99%

“…Inverse correlation between leptin and RBM28 patterns of expression in red junglefowl tissue suggest opposite regulatory function such as that reported in mammalian hair follicle in mammals, where RBM28 stimulates and leptin inhibits anagen-phase development [ 36 , 37 ]. This observation could help future studies of the interactions between leptin and RBM28.…”

Section: Discussionmentioning

confidence: 99%

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Mapping of leptin and its syntenic genes to chicken chromosome 1p

et al. 2017

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BackgroundMisidentification of the chicken leptin gene has hampered research of leptin signaling in this species for almost two decades. Recently, the genuine leptin gene with a GC-rich (~70%) repetitive-sequence content was identified in the chicken genome but without indicating its genomic position. This suggests that such GC-rich sequences are difficult to sequence and therefore substantial regions are missing from the current chicken genome assembly.ResultsA radiation hybrid panel of chicken-hamster Wg3hCl2 cells was used to map the genome location of the chicken leptin gene. Contrary to our expectations, based on comparative genome mapping and sequence characteristics, the chicken leptin was not located on a microchromosome, which are known to contain GC-rich and repetitive regions, but at the distal tip of the largest chromosome (1p). Following conserved synteny with other vertebrates, we also mapped five additional genes to this genomic region (ARF5, SND1, LRRC4, RBM28, and FLNC), bridging the genomic gap in the current Galgal5 build for this chromosome region. All of the short scaffolds containing these genes were found to consist of GC-rich (54 to 65%) sequences comparing to the average GC-content of 40% on chromosome 1. In this syntenic group, the RNA-binding protein 28 (RBM28) was in closest proximity to leptin. We deduced the full-length of the RBM28 cDNA sequence and profiled its expression patterns detecting a negative correlation (R = − 0.7) between the expression of leptin and of RBM28 across tissues that expressed at least one of the genes above the average level. This observation suggested a local regulatory interaction between these genes. In adipose tissues, we observed a significant increase in RBM28 mRNA expression in breeds with lean phenotypes.ConclusionMapping chicken leptin together with a cluster of five syntenic genes provided the final proof for its identification as the true chicken ortholog. The high GC-content observed for the chicken leptin syntenic group suggests that other similar clusters of genes in GC-rich genomic regions are missing from the current genome assembly (Galgal5), which should be resolved in future assemblies of the chicken genome.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-017-0543-1) contains supplementary material, which is available to authorized users.

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RBM28, a protein deficient in ANE syndrome, regulates hair follicle growth via miR‐203 and p63

Cited by 17 publications

References 46 publications

Improvement of epidermal covering on AEC patients with severe skin erosions by PRIMA-1MET/APR-246

Improvement of epidermal covering on AEC patients with severe skin erosions by PRIMA-1MET/APR-246

The molecular basis for ANE syndrome revealed by the large ribosomal subunit processome interactome

Mapping of leptin and its syntenic genes to chicken chromosome 1p

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