Feingold Syndrome Research Articles

MYCN in human development and diseases.

Somatic mutations in MYCN have been identified across various tumors, playing pivotal roles in tumorigenesis, tumor progression, and unfavorable prognoses. Despite its established notoriety as an oncogenic driver, there is a growing interest in exploring the involvement of MYCN in human development. While MYCN variants have traditionally been associated with Feingold syndrome type 1, recent discoveries highlight gain-of-function variants, specifically p.(Thr58Met) and p.(Pro60Leu), as the cause for megalencephaly-polydactyly syndrome. The elucidation of cellular and murine analytical data from both loss-of-function (Feingold syndrome model) and gain-of-function models (megalencephaly-polydactyly syndrome model) is significantly contributing to a comprehensive understanding of the physiological role of MYCN in human development and pathogenesis. This review discusses the MYCN's functional implications for human development by reviewing the clinical characteristics of these distinct syndromes, Feingold syndrome, and megalencephaly-polydactyly syndrome, providing valuable insights into the understanding of pathophysiological backgrounds of other syndromes associated with the MYCN pathway and the overall comprehension of MYCN's role in human development.

Gain-of-function MYCN causes a megalencephaly-polydactyly syndrome manifesting mirror phenotypes of Feingold syndrome

MYCN, a member of the MYC proto-oncogene family, regulates cell growth and proliferation. Somatic mutations of MYCN are identified in various tumors, and germline loss-of-function variants are responsible for Feingold syndrome, characterized by microcephaly. In contrast, one megalencephalic patient with a gain-of-function variant in MYCN, p.Thr58Met, has been reported, and additional patients and pathophysiological analysis are required to establish the disease entity. Herein, we report two unrelated megalencephalic patients with polydactyly harboring MYCN variants of p.Pro60Leu and Thr58Met, along with the analysis of gain-of-function and loss-of-function Mycn mouse models. Functional analyses for MYCN-Pro60Leu and MYCN-Thr58Met revealed decreased phosphorylation at Thr58, which reduced protein degradation mediated by FBXW7 ubiquitin ligase. The gain-of-function mouse model recapitulated the human phenotypes of megalencephaly and polydactyly, while brain analyses revealed excess proliferation of intermediate neural precursors during neurogenesis, which we determined to be the pathomechanism underlying megalencephaly. Interestingly, the kidney and female reproductive tract exhibited overt morphological anomalies, possibly as a result of excess proliferation during organogenesis. In conclusion, we confirm an MYCN gain-of-function-induced megalencephaly-polydactyly syndrome, which shows a mirror phenotype of Feingold syndrome, and reveal that MYCN plays a crucial proliferative role, not only in the context of tumorigenesis, but also organogenesis.

Abstract P3092: Histone Deacetylase 6 Inhibitor Suppresses The Inflammation Through MIR17HG In LPS-Induced Macrophages

Background: Long non-coding RNAs (lncRNAs) have been linked to a wide range of pathologic diseases despite having a limited capacity for protein coding. MIR17HG is the host gene for the miR17-92a-1 cluster, a group of six microRNAs involved in several cellular functions. Dysregulation of MIR17HG has been associated with multiple diseases such as Feingold Syndrome, osteoarthritis, Parkinson’s disease, and cancer. Treatment with histone deacetylase-6 inhibitor (Tubastatin A -TBA) reduces inflammatory response on macrophages after LPS challenge. Here, we analyze the role of MIR17HG as an epigenetic regulator of inflammation in LPS-induced THP1 cells. Hypothesis: We hypothesize that TBA suppresses the effect of MIR17HG and promotes protection in macrophages under LPS-induced inflammation. Methods and Results: To elucidate potential lncRNAs of interest during macrophage inflammatory response, we treated macrophages with LPS (1 μg/mL) and TBA (2.5 μM) for 1hr and performed RNA sequencing. We selected MIR17HG for further investigation based on the sequencing data (Fig. A) and bioinformatic analysis. The expression of MIR17HG in LPS and TBA treatment conditions was validated by qRT-PCR. MIR17HG expression was significantly higher in LPS and treatment with TBA suppressed the LPS-stimulated MIR17HG expression (Fig. B, C) . We also observed the IL1β behaved in a similar manner (Fig. D) . Further overexpression and knockdown experiments will be performed to identify the link between MIR17HG and ILβ. Conclusion: We report for the first time that MIR17HG is an important mediator of the pro-inflammatory response of macrophages.

Mycn regulates intestinal development through ribosomal biogenesis in a zebrafish model of Feingold syndrome 1.

Feingold syndrome type 1, caused by loss-of-function of MYCN, is characterized by varied phenotypes including esophageal and duodenal atresia. However, no adequate model exists for studying the syndrome's pathological or molecular mechanisms, nor is there a treatment strategy. Here, we developed a zebrafish Feingold syndrome type 1 model with nonfunctional mycn, which had severe intestinal atresia. Single-cell RNA-seq identified a subcluster of intestinal cells that were highly sensitive to Mycn, and impaired cell proliferation decreased the overall number of intestinal cells in the mycn mutant fish. Bulk RNA-seq and metabolomic analysis showed that expression of ribosomal genes was down-regulated and that amino acid metabolism was abnormal. Northern blot and ribosomal profiling analysis showed abnormal rRNA processing and decreases in free 40S, 60S, and 80S ribosome particles, which led to impaired translation in the mutant. Besides, both Ribo-seq and western blot analysis showed that mTOR pathway was impaired in mycn mutant, and blocking mTOR pathway by rapamycin treatment can mimic the intestinal defect, and both L-leucine and Rheb, which can elevate translation via activating TOR pathway, could rescue the intestinal phenotype of mycn mutant. In summary, by this zebrafish Feingold syndrome type 1 model, we found that disturbance of ribosomal biogenesis and blockage of protein synthesis during development are primary causes of the intestinal defect in Feingold syndrome type 1. Importantly, our work suggests that leucine supplementation may be a feasible and easy treatment option for this disease.

Retrospective evaluation of clinical and molecular data of 148 cases of esophageal atresia.

Developmental abnormalities provide a unique opportunity to seek for the molecular mechanisms underlying human organogenesis. Esophageal development remains incompletely understood and elucidating causes for esophageal atresia (EA) in humans would contribute to achieve a better comprehension. Prenatal detection, syndromic classification, molecular diagnosis, and prognostic factors in EA are challenging. Some syndromes have been described to frequently include EA, such as CHARGE, EFTUD2-mandibulofacial dysostosis, Feingold syndrome, trisomy 18, and Fanconi anemia. However, no molecular diagnosis is made in most cases, including frequent associations, such as Vertebral-Anal-Cardiac-Tracheo-Esophageal-Renal-Limb defects (VACTERL). This study evaluates the clinical and genetic test results of 139 neonates and 9 fetuses followed-up at the Necker-Enfants Malades Hospital over a 10-years period. Overall, 52 cases were isolated EA (35%), and 96 were associated with other anomalies (65%). The latter group is divided into three subgroups: EA with a known genomic cause (9/148, 6%); EA with Vertebral-Anal-Cardiac-Tracheo-Esophageal-Renal-Limb defects (VACTERL) or VACTERL/Oculo-Auriculo-Vertebral Dysplasia (VACTERL/OAV) (22/148, 14%); EA with associated malformations including congenital heart defects, duodenal atresia, and diaphragmatic hernia without known associations or syndromes yet described (65/148, 44%). Altogether, the molecular diagnostic rate remains very low and may underlie frequent non-Mendelian genetic models.

Innovative management of severe tracheobronchomalacia using anterior and posterior tracheobronchopexy.

Combined anterior and posterior tracheobronchopexy is a novel surgical approach for the management of severe tracheobronchomalacia (TBM). We present our institutional experience with this procedure. Our objective was to determine the utility and safety of anterior and posterior tracheopexy in the treatment of severe TBM. Retrospective chart review. All patients who underwent anterior and posterior tracheopexy from January 2013 to July 2017 were retrospectively reviewed. Charts were reviewed for indications, preoperative work-up, tracheobronchomalacia classification and severity, procedure, associated syndromes, synchronous upper aerodigestive tract lesions, and aberrant thoracic vessels. Main outcomes measured included improvement in respiratory symptoms, successful extubation and/or decannulation, vocal fold immobility, and new tracheotomy placement. Twenty-five patients underwent anterior and posterior tracheopexy at a mean age of 15.8 months (range, 2-209 months; mean, 31 months if 2 outliers of 206 and 209 months included). Mean length of follow-up was 26.8 months (range, 13-52 months). Indications for surgery included apneic events, ventilator dependence, need for positive pressure ventilation, tracheotomy dependence secondary to TBM, recurrent pneumonia, and exercise intolerance. Many patients had other underlying syndromes and synchronous upper aerodigestive tract lesions (8 VACTERL, 2 CHARGE, 1 trisomy 21, 1 Feingold syndrome, 17 esophageal atresia/tracheoesophageal fistula, 20 cardiac/great vessel anomalies, 1 subglottic stenosis, 1 laryngomalacia, 7 laryngeal cleft). At preoperative bronchoscopy, 21 of 25 patients had >90% collapse of at least one segment of their trachea, and the remaining four had 70% to 90% collapse. Following anterior and posterior tracheopexy, one patient developed new bilateral vocal-fold immobility; one patient with a preoperative left cord paralysis had a new right vocal-fold immobility. Postoperatively, most patients had significant improvement in their respiratory symptoms (21 of 25, 84%) at most recent follow-up. Three patients with preexisting tracheotomy were decannulated; two patients still had a tracheotomy at last follow-up. Two patients required new tracheotomy for bilateral vocal-fold immobility. Combined anterior and posterior tracheopexy is a promising new technique for the surgical management of severe TBM. Further experience and longer follow-up are needed to validate this contemporary approach and to minimize the risk of recurrent laryngeal nerve injury. 4 Laryngoscope, 130:E65-E74, 2020.

MYCN de novo gain-of-function mutation in a patient with a novel megalencephaly syndrome

BackgroundIn this study, we aimed to identify the gene abnormality responsible for pathogenicity in an individual with an undiagnosed neurodevelopmental disorder with megalencephaly, ventriculomegaly, hypoplastic corpus callosum, intellectual disability, polydactyly...

Distinct molecular pathways mediate Mycn and Myc-regulated miR-17-92 microRNA action in Feingold syndrome mouse models

Feingold syndrome is a skeletal dysplasia caused by loss-of-function mutations of either MYCN (type 1) or MIR17HG that encodes miR-17-92 microRNAs (type 2). Since miR-17-92 expression is transcriptionally regulated by MYC transcription factors, it has been postulated that Feingold syndrome type 1 and 2 may be caused by a common molecular mechanism. Here we show that Mir17-92 deficiency upregulates TGF-β signaling, whereas Mycn-deficiency downregulates PI3K signaling in limb mesenchymal cells. Genetic or pharmacological inhibition of TGF-β signaling efficiently rescues the skeletal defects caused by Mir17-92 deficiency, suggesting that upregulation of TGF-β signaling is responsible for the skeletal defect of Feingold syndrome type 2. By contrast, the skeletal phenotype of Mycn-deficiency is partially rescued by Pten heterozygosity, but not by TGF-β inhibition. These results strongly suggest that despite the phenotypical similarity, distinct molecular mechanisms underlie the pathoetiology for Feingold syndrome type 1 and 2.

Rare health conditions 10: Tangier disease, glioblastoma multiforme, Feingold syndrome

The purpose of this series is to briefly highlight a range of rare health conditions. Rare health conditions are those who affect no more and usually less than 1 person in every 2000 and many HCAs and nurses will encounter some of these conditions given the high number of these conditions. This tenth article will briefly explore three more of these conditions.

MP07-02 POLYA TAG LIBRARY PREPARATION FOR NEW GENERATION SEQUENCING (NGS) IN HUMAN TESTIS FAILS TO DETECT NON-CODING AND TRANSLATED RNAS IMPORTANT IN TESTICULAR FUNCTION AS COMPARED TO RIBOSOMAL RNA DEPLETION METHOD.

You have accessJournal of UrologyInfertility: Basic Research & Pathophysiology I1 Apr 2017MP07-02 POLYA TAG LIBRARY PREPARATION FOR NEW GENERATION SEQUENCING (NGS) IN HUMAN TESTIS FAILS TO DETECT NON-CODING AND TRANSLATED RNAS IMPORTANT IN TESTICULAR FUNCTION AS COMPARED TO RIBOSOMAL RNA DEPLETION METHOD. Ryan Flannigan, Anna Mielnik, Alex Bolyakov, Phil V. Bach, Peter Schlegel, and Darius Paduch Ryan FlanniganRyan Flannigan More articles by this author , Anna MielnikAnna Mielnik More articles by this author , Alex BolyakovAlex Bolyakov More articles by this author , Phil V. BachPhil V. Bach More articles by this author , Peter SchlegelPeter Schlegel More articles by this author , and Darius PaduchDarius Paduch More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.268AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Non-coding RNAs (ncRNAs) are emerging as important but poorly understood regulators of mRNA transcription and translation. However, common library preparation techniques for RNA sequencing selects for coding mRNAs by the presence of a poly-A tail; thus, by excluding non-PolyA ncRNAs, many biologically significant transcripts may be overlooked by using this method. The objective of this study was to evaluate differences in testicular RNA identification using 2 different methods of library preparation: polyA and ribosomal RNA depletion (RibZero) using Illumina kits. METHODS Total RNA was extracted from 3 human testis samples and processed using two different methods of library preparations: one based on polyA tags, and the other on depletion of ribosomal RNAs. The cDNA libraries were then sequenced at the same depth and annotated to known published databases. Identified transcripts were divided into two groups based on presence in one of the library preparation methods but not the other. Clinical and biological significance of identified genes was examined using the DAVID. Failure of detection of RibZero-only genes by RNAseq using polyA preparation was then confirmed by analyzing results of RNAseq in 64 testicular samples from normal patients, men with sertoli cell only (SCO), early and late maturation arrest and hypospermatogenesis. RESULTS 61 genes were detected only using polyA method with no detection in RibZero group (p=0.05): 17 of them belonged to small nuclear RNAs (snRNAs), 12 were snRNAs hosting genes, 3 humanin like proteins, and 3 were miRNA hosting genes: MIR137HG, MIR17HG, MIRLET7DHG. Deletion of MIR17HG leads to Feingold syndrome in humans and animal models. 74 genes were identified exclusively in RibZero group and not identified in the polyA group. The top 4 genes identified exclusively by RibZero were TAS2R50, MAGI1-AS, HIST1H3I, HIST1H4K. HIST1H4K was then further analyzed and its expression was highly abundant and specific to pachytene spermatocytes. Important components of the miRNA processing complex: AGO1,2, and 3 were expressed at >2x higher level (p=0.03) in ribosomal RNA library depletion preparation then polyA prep. CONCLUSIONS PolyA tail RNA enrichment method fails to adequately detect at least 7% of important RNAs in the human testis. Including ribosomal depletion RNA library preparation in addition to polyA tags enrichment is an important step to more comprehensively evaluate ncRNAs and testicular function. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e82 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Ryan Flannigan More articles by this author Anna Mielnik More articles by this author Alex Bolyakov More articles by this author Phil V. Bach More articles by this author Peter Schlegel More articles by this author Darius Paduch More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

A case of Feingold type 2 syndrome associated with keratoconus refines keratoconus type 7 locus on chromosome 13q

We report on a 58-year old woman with microcephaly, mild dysmorphic features, bilateral keratoconus, digital abnormalities, short stature and mild cognitive delay. Except for keratoconus, the phenotype was suggestive for Feingold syndrome type 2 (FGLDS2, MIM 614326), a rare autosomal dominant disorder described in six patients worldwide, due to the haploinsufficiency of MIR17HG, a micro RNA encoding gene. Karyotype showed a de novo deletion on chromosome 13q, further defined by array-Comparative Genomic Hybridization (a-CGH) to a 17.2-Mb region. The deletion included MIR17HG, as expected by the FGLDS2 phenotype, and twelve genes from the keratoconus type 7 locus. Because our patient presented with keratoconus, we propose she further refines disease genes at this locus. Among previously suggested candidates, we exclude DOCK9 and STK24, and propose as best candidates IPO5, DNAJC3, MBNL2 and RAP2A.In conclusion, we report a novel phenotypic association of Feingold syndrome type 2 and keratoconus, a likely contiguous gene syndrome due to a large genomic deletion on 13q spanning MIR17HG and a still to be identified gene for keratoconus.

Neurobehavioral Alterations in a Genetic Murine Model of Feingold Syndrome 2.

Feingold syndrome (FS) is an autosomal dominant disorder characterized by microcephaly, short stature, digital anomalies, esophageal/duodenal atresia, facial dysmorphism, and various learning disabilities. Heterozygous deletion of the miR-17-92 cluster is responsible for a subset of FS (Feingold syndrome type 2, FS2), and the developmental abnormalities that characterize this disorder are partially recapitulated in mice that harbor a heterozygous deletion of this cluster (miR-17-92∆/+ mice). Although Feingold patients develop a wide array of learning disabilities, no scientific description of learning/cognitive disabilities, intellectual deficiency, and brain alterations have been described in humans and animal models of FS2. The aim of this study was to draw a behavioral profile, during development and in adulthood, of miR-17-92∆/+ mice, a genetic mouse model of FS2. Moreover, dopamine, norepinephrine and serotonin tissue levels in the medial prefrontal cortex (mpFC), and Hippocampus (Hip) of miR-17-92∆/+ mice were analyzed.Our data showed decreased body growth and reduced vocalization during development. Moreover, selective deficits in spatial ability, social novelty recognition and memory span were evident in adult miR-17-92∆/+ mice compared with healthy controls (WT). Finally, we found altered dopamine as well as serotonin tissue levels, in the mpFC and Hip, respectively, of miR-17-92∆/+ in comparison with WT mice, thus suggesting a possible link between cognitive deficits and altered brain neurotransmission.

17. Feingold's Syndrome as an Unusual Mimic of Rheumatoid Arthritis

17. Feingold's Syndrome as an Unusual Mimic of Rheumatoid Arthritis

MicroRNA-17~92 Is Required for Nephrogenesis and Renal Function

Deletion of all microRNAs (miRNAs) in nephron progenitors leads to premature loss of these cells, but the roles of specific miRNAs in progenitors have not been identified. Deletions in the MIR17HG cluster (miR-17~92 in mice), detected in a subset of patients with Feingold syndrome, represent the first miRNA mutations to be associated with a developmental defect in humans. Although MIR17HG is expressed in the developing kidney, and patients with Feingold syndrome caused by MYCN mutations have renal anomalies, it remains unclear to what extent MIR17HG contributes to renal development and function. To define the role of miR-17~92, we generated mice with a conditional deletion of miR-17~92 in nephron progenitors and their derivatives. The nephron progenitor population was preserved in these mice; however, this deletion impaired progenitor cell proliferation and reduced the number of developing nephrons. Postnatally, mutant mice developed signs of renal disease, including albuminuria by 6 weeks and focal podocyte foot process effacement and glomerulosclerosis at 3 months. Taken together, these data support a role for this miRNA cluster in renal development, specifically in the regulation of nephron development, with subsequent consequences for renal function in adult mice.

Exudative retinopathy, cerebral calcifications, duodenal atresia, preaxial polydactyly, micropenis, microcephaly and short stature: A new syndrome?

The association of Coats disease with intrauterine growth retardation, intracranial calcification, leukodystrophy, brain cysts, osteopenia, and gastrointestinal bleeding defines Coats plus syndrome caused by mutations in the CTC1 gene, encoding conserved telomere maintenance component 1. Here, we report on a child with exudative retinopathy, cerebral calcifications, duodenal atresia, preaxial polydactyly, micropenis, microcephaly, and short stature, in whom no mutations in CTC1 were found. Our patient shares some features seen in other diseases associated with telomere shortening including Hoyeraal-Hreidarsson and Revesz syndromes. We therefore measured telomere length by Flow-Fish which was normal. The association of duodenal atresia and microcephaly also suggested a diagnosis of Feingold syndrome. However, direct sequencing of MYCN was normal, and we did not detect any hemizygous deletion of the miR-17∼92 polycistronic miRNA cluster. To our knowledge, the phenotype we report on has not been described previously, leading us to speculate that this condition may represent a new syndrome.

MicroRNA-17-92 cluster regulates osteoblast proliferation and differentiation

MicroRNAs (miRNAs) have been identified to play important functions during osteoblast proliferation, differentiation, and apoptosis. The miR-17~92 cluster is highly conserved in all vertebrates. Loss-of-function of the miR-17-92 cluster results in smaller embryos and immediate postnatal death of all animals. Germline hemizygous deletions of MIR17HG are accounted for microcephaly, short stature, and digital abnormalities in a few cases of Feingold syndrome. These reports indicate that miR-17~92 may play important function in skeletal development and mature. To determine the functional roles of miR-17~92 in bone metabolism as well as osteoblast proliferation and differentiation. Murine embryonic stem cells D3 and osteoprogenitor cell line MC3T3-E1 were induced to differentiate into osteoblasts; the expression of miR-17-92 was assayed by quantitative real-time RT-PCR. The skeletal phenotypes were assayed in mice heterozygous for miR-17~92 (miR-17~92 (+/Δ) ). To determine the possibly direct function of miR-17~92 in bone cells, osteoblasts from miR-17~92 (+/Δ) mice were investigated by ex vivo cell culture. miR-17, miR-92a, and miR-20a within miR-17-92 cluster were expressed at high level in bone tissue and osteoblasts. The expression of miR-17-92 was down-regulated along with osteoblast differentiation, the lowest level was found in mature osteoblasts. Compared to wildtype controls, miR-17-92 (+/Δ) mice showed significantly lower trabecular and cortical bone mineral density, bone volume and trabecular number at 10weeks old. mRNA expression of Runx2 and type I collagen was significantly lower in bone from miR-17-92 (+/Δ) mice. Osteoblasts from miR-17-92 (+/Δ) mice showed lower proliferation rate, ALP activity and less calcification. Our research suggests that the miR-17-92 cluster critically regulates bone metabolism, and this regulation is mostly through its function in osteoblasts.

Myocardial Mycn is essential for mouse ventricular wall morphogenesis

MYCN is a highly conserved transcription factor with multifaceted roles in development and disease. Mutations in MYCN are associated with Feingold syndrome, a developmental disorder characterized in part by congenital heart defects. Mouse models have helped elucidate MYCN functions; however its cardiac-specific roles during development remain unclear. We employed a Cre/loxp strategy to uncover the specific activities of MYCN in the developing mouse myocardium. Myocardial deletion of Mycn resulted in a thin-myocardial wall defect with dramatically reduced trabeculation. The mutant heart defects strongly resemble the phenotype caused by disruption of BMP10 and Neuregulin-1 (NRG1) signaling pathways, two central mediators of myocardial wall development. Our further examination showed that expression of MYCN is regulated by both BMP and NRG1 signaling. The thin-wall defect in mutant hearts is caused by a reduction in both cell proliferation and cell size. MYCN promotes cardiomyocyte proliferation through regulating expression of cell cycle regulators (including CCND1, CCND2, and ID2) and promotes cardiomyocyte growth through regulating expression of p70S6K. In addition, expression of multiple sarcomere proteins is altered in Mycn myocardial-inactivation embryos, indicating its essential role for proper cardiomyocyte differentiation. In summary, Mycn acts downstream of BMP and NRG1 cardiogenic signaling pathways to promote normal myocardial wall morphogenesis.

A de novo 4.4-Mb microdeletion in 2p24.3 → p24.2 in a girl with bilateral hearing impairment, microcephaly, digit abnormalities and Feingold syndrome

We report a 26-month-old girl with profound hearing impairment, microcephaly, psychomotor retardation, short palpebral fissures, hypertelorism, epicanthic folds, a broad nasal bridge, anteverted nostrils, large low-set ears, micrognathia, brachymesophalangy of the second and the fifth fingers, clinodactyly of bilateral fifth fingers and a wide interdigital space between the first and the second toes, carrying a 4.4-Mb de novo microdeletion of chromosome 2p24.3 → p24.2. This region contains the genes of FAM84A, NBAS, DDX1, MYCNOS and MYCN, of which haploinsufficiency or mutations of the MYCN gene is associated with Feingold syndrome. Brain magnetic resonance imaging revealed cochlear nerve hypoplasia and internal auditory canal stenosis. Temporal bone computed tomography showed abnormal dilation of bilateral vestibular and lateral semicircular canals. The present case provides evidence that haploinsufficiency of MYCN in 2p24.3 deletion in humans can cause structural and functional abnormalities of the inner ear.

Germline deletion of the miR-17∼92 cluster causes skeletal and growth defects in humans

MicroRNAs (miRNAs) are key regulators of gene expression in animals and plants. Studies in a variety of model organisms show that miRNAs modulate developmental processes. To our knowledge, the only hereditary condition known to be caused by a miRNA is a form of adult-onset non-syndromic deafness, and no miRNA mutation has yet been found to be responsible for any developmental defect in humans. Here we report the identification of germline hemizygous deletions of MIR17HG, encoding the miR-17∼92 polycistronic miRNA cluster, in individuals with microcephaly, short stature and digital abnormalities. We demonstrate that haploinsufficiency of miR-17∼92 is responsible for these developmental abnormalities by showing that mice harboring targeted deletion of the miR-17∼92 cluster phenocopy several key features of the affected humans. These findings identify a regulatory function for miR-17∼92 in growth and skeletal development and represent the first example of an miRNA gene responsible for a syndromic developmental defect in humans.

Genetic Factors in Isolated and Syndromic Esophageal Atresia

Genetic Factors in Isolated and Syndromic Esophageal Atresia