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  1. Article: A Dynamic 3D Aggregate-Based System for the Successful Expansion and Neural Induction of Human Pluripotent Stem Cells.

    Miranda, Cláudia C / Akenhead, Michael L / Silva, Teresa P / Derr, Michael A / Vemuri, Mohan C / Cabral, Joaquim M S / Fernandes, Tiago G

    Frontiers in cellular neuroscience

    2022  Volume 16, Page(s) 838217

    Abstract: The demand for large cell numbers for cellular therapies and drug screening applications requires the development of scalable platforms capable of generating high-quality populations of tissue-specific cells derived from human pluripotent stem cells ( ... ...

    Abstract The demand for large cell numbers for cellular therapies and drug screening applications requires the development of scalable platforms capable of generating high-quality populations of tissue-specific cells derived from human pluripotent stem cells (hPSCs). Here, we studied the ability of Gibco StemScale PSC Suspension Medium to promote the efficient expansion of hPSC cultures as aggregates grown in suspension. We tested human induced pluripotent stem cell (hiPSC) growth in 6-well plates (on orbital shaker platforms) and single-use vertical-wheel bioreactors for a total of three consecutive passages. Up to a 9-fold increase in cell number was observed over 5 days per passage, with a cumulative fold change up to 600 in 15 days. Additionally, we compared neural induction of hiPSCs by using a dual SMAD inhibition protocol with a commercially available neural induction medium, which can potentially yield more than a 30-fold change, including neural progenitor induction and expansion. This system can also be adapted toward the generation of floor plate progenitors, which yields up to an 80-fold change in cell number and generates FOXA2-positive populations. In summary, we developed platforms for hiPSC expansion and neural induction into different brain regions that provide scalability toward producing clinically relevant cell numbers.
    Language English
    Publishing date 2022-03-03
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2452963-1
    ISSN 1662-5102
    ISSN 1662-5102
    DOI 10.3389/fncel.2022.838217
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Current issues on molecular diagnosis of GH signaling defects.

    Feigerlova, Eva / Hwa, Vivian / Derr, Michael A / Rosenfeld, Ron G

    Endocrine development

    2013  Volume 24, Page(s) 118–127

    Abstract: The growth-promoting effects of GH are mediated primarily by regulating the biosynthesis of insulin-like growth factor (IGF)-1. The binding of circulating GH to the cell surface GH receptor (GHR) initiates signaling cascades, of which the signal ... ...

    Abstract The growth-promoting effects of GH are mediated primarily by regulating the biosynthesis of insulin-like growth factor (IGF)-1. The binding of circulating GH to the cell surface GH receptor (GHR) initiates signaling cascades, of which the signal transducer and activator of transcription (STAT)-5b pathway has proven, in both rodent models and human case studies, to be the most critical in regulating IGF-1 production. The identification of rare inactivating STAT5B mutations in children, whose severe postnatal growth retardation was associated with GH insensitivity (GHI) and IGF-1 deficiency, confirmed the importance of STAT5b in regulating IGF-1 gene expression. Unlike GHI due to mutations in the GHR gene, patients carrying STAT5B mutations often present with immune dysfunction that can lead to severe, life-threatening infections and chronic pulmonary disease, consistent with the fact that STAT5b is activated by multiple cytokines involved in immunity. The possibility of a STAT5b disorder should be considered, therefore, when children present with chronic infection and/or unexplained pulmonary disease concomitant with severe postnatal growth failure.
    MeSH term(s) Animals ; Child ; Female ; Growth Disorders/diagnosis ; Growth Disorders/genetics ; Growth Hormone/deficiency ; Growth Hormone/genetics ; Growth Hormone/metabolism ; Humans ; Insulin-Like Growth Factor I/deficiency ; Insulin-Like Growth Factor I/genetics ; Insulin-Like Growth Factor I/metabolism ; Male ; Models, Biological ; Receptors, Somatotropin/genetics ; Receptors, Somatotropin/metabolism ; Rodentia ; STAT5 Transcription Factor/genetics ; Signal Transduction/genetics
    Chemical Substances Receptors, Somatotropin ; STAT5 Transcription Factor ; Insulin-Like Growth Factor I (67763-96-6) ; Growth Hormone (9002-72-6)
    Language English
    Publishing date 2013
    Publishing country Switzerland
    Document type Journal Article ; Review
    ISSN 1662-2979 ; 1421-7082
    ISSN (online) 1662-2979
    ISSN 1421-7082
    DOI 10.1159/000342586
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: IGF-I in human growth: lessons from defects in the GH-IGF-I axis.

    Hwa, Vivian / Fang, Peng / Derr, Michael A / Fiegerlova, Eva / Rosenfeld, Ron G

    Nestle Nutrition Institute workshop series

    2013  Volume 71, Page(s) 43–55

    Abstract: The IGF system plays a critical role in all phases of human growth, including intrauterine, childhood and pubertal. The importance of IGF-I for both in utero as well as postnatal human growth is highlighted by rare human homozygous IGF1 mutations, which ... ...

    Abstract The IGF system plays a critical role in all phases of human growth, including intrauterine, childhood and pubertal. The importance of IGF-I for both in utero as well as postnatal human growth is highlighted by rare human homozygous IGF1 mutations, which are characterized by intrauterine growth retardation (IUGR), microcephaly, mental retardation and severe postnatal growth failure. Clinical conditions of IGF-I resistance due to mutations in the IGF-I receptor (IGFIR) similarly lead to IUGR and postnatal growth retardation. Postnatal regulation of IGF-I production is predominantly GH dependent. Defects in the GH-IGF-I axis, including mutations in the GHR, STAT5B and IGFALS genes, lead to postnatal IGF deficiency and GH insensitivity. Patients are of normal birth size but present with severe postnatal growth failure, despite normal or elevated levels of GH. Other phenotypic features - immune deficiency for STAT5B defects and insulin insensitivity for IGFALS defects - are of note. Mutations identified have been predominantly recessive. The identification and assessment of genetic defects in the GH-IGF axis has greatly enhanced our understanding of the critical importance of IGF-I in human linear growth. Continued evaluations will facilitate better diagnosis and management of children presenting with abnormal growth and development.
    MeSH term(s) Carrier Proteins/genetics ; Carrier Proteins/metabolism ; Child ; Fetal Growth Retardation/genetics ; Glycoproteins/genetics ; Glycoproteins/metabolism ; Humans ; Immunologic Deficiency Syndromes/genetics ; Insulin Resistance/genetics ; Insulin-Like Growth Factor I/deficiency ; Insulin-Like Growth Factor I/genetics ; Insulin-Like Growth Factor I/physiology ; Intellectual Disability/genetics ; Microcephaly/genetics ; Mutation ; Receptor, IGF Type 1/genetics ; Receptor, IGF Type 1/metabolism ; STAT5 Transcription Factor/genetics ; STAT5 Transcription Factor/metabolism
    Chemical Substances Carrier Proteins ; Glycoproteins ; STAT5 Transcription Factor ; STAT5B protein, human ; insulin-like growth factor binding protein, acid labile subunit ; somatotropin-binding protein ; Insulin-Like Growth Factor I (67763-96-6) ; Receptor, IGF Type 1 (EC 2.7.10.1)
    Language English
    Publishing date 2013
    Publishing country Switzerland
    Document type Journal Article
    ISSN 1664-2155
    ISSN (online) 1664-2155
    DOI 10.1159/000342548
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Severe short stature caused by novel compound heterozygous mutations of the insulin-like growth factor 1 receptor (IGF1R).

    Fang, Peng / Cho, Yoon Hi / Derr, Michael A / Rosenfeld, Ron G / Hwa, Vivian / Cowell, Christopher T

    The Journal of clinical endocrinology and metabolism

    2012  Volume 97, Issue 2, Page(s) E243–7

    Abstract: Context: IGF-I, essential for normal human growth in utero and postnatally, mediates its effects through the IGF-I receptor (IGF1R). More than nine heterozygous mutations, including one compound heterozygous mutation, of the IGF1R gene have been ... ...

    Abstract Context: IGF-I, essential for normal human growth in utero and postnatally, mediates its effects through the IGF-I receptor (IGF1R). More than nine heterozygous mutations, including one compound heterozygous mutation, of the IGF1R gene have been reported in patients with varying degrees of intrauterine and postnatal growth retardation.
    Objective: The objective of the study was the analysis of the IGF1R gene in a short-statured patient.
    Patient: The male patient, with a height of -5.91 sd score (aged 20.3 yr), had consistently elevated circulating serum concentrations of IGF-I. A diagnosis of antibody-negative insulin-requiring diabetes was made at age 14 yr. His deceased sister was also severely short statured (-3.75 sd score).
    Results: The patient and his sister carried novel, compound heterozygous IGF1R missense mutations, E121K (exon 2) and E234K (exon 3), inherited from the mother and father, respectively. In vitro reconstitution studies demonstrated that neither the E121K nor E234K mutation affected IGF1R prepeptide expression, but levels of the proteolytically cleaved α- and β-subunit were consistently low. As a consequence, each IGF1R variant exhibited significantly reduced IGF-I-induced signal transduction. Correlating to these studies, expression of functional IGF1R and the IGF-I-induced activation of the IGF1R pathway were markedly reduced in the primary dermal fibroblasts established from the patient.
    Conclusions: Only the second compound heterozygous IGF1R mutations to be identified, the p.E121K/E234K variant is the cause of intrauterine growth retardation and the most severe postnatal growth failure described to date in a patient with IGF1R defects. Whether the mutant IGF1R also contributes to the diabetic phenotype, however, remains to be determined.
    MeSH term(s) Child, Preschool ; Dwarfism/genetics ; Fatal Outcome ; Female ; Genetic Predisposition to Disease ; HEK293 Cells ; Heterozygote ; Humans ; Male ; Mutation, Missense/physiology ; Receptor, IGF Type 1/genetics ; Severity of Illness Index ; Siblings ; Young Adult
    Chemical Substances Receptor, IGF Type 1 (EC 2.7.10.1)
    Language English
    Publishing date 2012-02
    Publishing country United States
    Document type Case Reports ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 3029-6
    ISSN 1945-7197 ; 0021-972X
    ISSN (online) 1945-7197
    ISSN 0021-972X
    DOI 10.1210/jc.2011-2142
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: A novel Y332C missense mutation in the intracellular domain of the human growth hormone receptor does not alter STAT5b signaling: redundancy of GHR intracellular tyrosines involved in STAT5b signaling.

    Derr, Michael A / Fang, Peng / Sinha, Sunil K / Ten, Svetlana / Hwa, Vivian / Rosenfeld, Ron G

    Hormone research in paediatrics

    2011  Volume 75, Issue 3, Page(s) 187–199

    Abstract: Background: The growth hormone receptor (GHR), upon binding with GH, induces JAK2-mediated phosphorylation of GHR intracellular tyrosines, which then recruit STAT5b. Aberrancies in STAT5b signaling, due to mutations in GHR or STAT5b genes, result in ... ...

    Abstract Background: The growth hormone receptor (GHR), upon binding with GH, induces JAK2-mediated phosphorylation of GHR intracellular tyrosines, which then recruit STAT5b. Aberrancies in STAT5b signaling, due to mutations in GHR or STAT5b genes, result in poor responses to GH and severe short stature.
    Objective: To evaluate and compare the role of a novel Y332C GHR variant identified in a patient with short stature to the other GHR intracellular tyrosines in the GHR-STAT5b signaling process.
    Results: Recombinant human GHR constructs carrying Y332C or single Y to F changes for each of the 7 intracellular tyrosines did not alter GH-induced GHR-STAT5b signaling in reconstitution studies. However, GH-induced STAT5b activation was specifically abrogated in an hGHR variant in which all 7 tyrosines were inactivated (MYF). When hGHR variants carrying single intracellular tyrosines were evaluated, STAT5b activation was comparable to that of wild-type hGHR only with variants carrying Y534, Y566 or Y627.
    Conclusion: We provide evidence that in human GHR, 3 intracellular tyrosines are critical and redundant in the GH-induced STAT5b signaling process. This redundancy may explain why an Y332C variant did not alter STAT5b signaling. Identification of missense variants in human GHR intracellular domain should be interpreted with caution and rigorously analyzed.
    MeSH term(s) Adolescent ; Amino Acid Sequence ; Amino Acid Substitution ; Genes, Reporter ; HEK293 Cells ; Humans ; Laron Syndrome/genetics ; Laron Syndrome/metabolism ; Male ; Mutagenesis, Site-Directed ; Mutant Proteins/metabolism ; Mutation, Missense ; Protein Structure, Tertiary ; Receptors, Somatotropin/chemistry ; Receptors, Somatotropin/genetics ; Receptors, Somatotropin/metabolism ; Recombinant Fusion Proteins/metabolism ; STAT5 Transcription Factor/metabolism ; Sequence Alignment ; Signal Transduction ; Tyrosine/metabolism
    Chemical Substances Mutant Proteins ; Receptors, Somatotropin ; Recombinant Fusion Proteins ; STAT5 Transcription Factor ; STAT5B protein, human ; Tyrosine (42HK56048U)
    Language English
    Publishing date 2011
    Publishing country Switzerland
    Document type Case Reports ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2537278-6
    ISSN 1663-2826 ; 1663-2818
    ISSN (online) 1663-2826
    ISSN 1663-2818
    DOI 10.1159/000320461
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  6. Article ; Online: The growth hormone receptor (GHR) c.899dupC mutation functions as a dominant negative: insights into the pathophysiology of intracellular GHR defects.

    Derr, Michael A / Aisenberg, Javier / Fang, Peng / Tenenbaum-Rakover, Yardena / Rosenfeld, Ron G / Hwa, Vivian

    The Journal of clinical endocrinology and metabolism

    2011  Volume 96, Issue 11, Page(s) E1896–904

    Abstract: Context: GH insensitivity (GHI) is a condition characterized by pronounced IGF-I deficiency and severe short stature. We previously identified a novel compound heterozygous GH receptor (GHR) mutation, GHR:p.R229H/c.899dupC, in a patient presenting with ... ...

    Abstract Context: GH insensitivity (GHI) is a condition characterized by pronounced IGF-I deficiency and severe short stature. We previously identified a novel compound heterozygous GH receptor (GHR) mutation, GHR:p.R229H/c.899dupC, in a patient presenting with GHI. The heterozygous p.R229H (prepeptide) variant was previously associated with GHI despite a lack of adequate functional studies. The novel heterozygous GHR:c.899dupC variant affects the critical JAK2-binding Box 1 region of the GHR intracellular domain; the duplication predicted a frameshift and early protein termination.
    Objective: The individual and synergistic effect(s) of the p.R229H and c.899dupC mutations on GHR function(s) were evaluated in reconstitution studies.
    Results: The recombinant human GHR (hGHR):p.R229H variant was readily expressed, and unexpectedly, GH-induced signal transducer and activator of transcription 5b (STAT5b) phosphorylation was comparable to that induced by wild-type hGHR. The truncated, immunodetected hGHR:c.899dupC variant, in contrast, was unresponsive to GH. To mimic a compound heterozygous state, the two variants were coexpressed, and strikingly, the presence of the hGHR:c.899dupC effectively abolished the GH-induced STAT5b activities that were observed with hGHR:p.R229H alone. Furthermore, hGHR:c.899dupC dose-dependently reduced the GH-induced STAT5b activities associated with hGHR:p.R229H. This dominant negative effect was also observed when hGHR:c.899dupC was coexpressed with wild-type hGHR.
    Conclusion: The p.R229H variant, contrary to an earlier report, appeared to function like wild-type GHR and, therefore, is unlikely to cause GHI. The c.899dupC variant is a novel dominant negative mutation that disrupted normal GHR signaling and is the cause for the GHI phenotype of the reported patient.
    MeSH term(s) HEK293 Cells ; Humans ; Insulin-Like Growth Factor I/deficiency ; Laron Syndrome/genetics ; Laron Syndrome/metabolism ; Mutation ; Phosphorylation/genetics ; Receptors, Somatotropin/genetics ; Receptors, Somatotropin/metabolism ; STAT5 Transcription Factor/genetics ; STAT5 Transcription Factor/metabolism ; Signal Transduction/genetics
    Chemical Substances Receptors, Somatotropin ; STAT5 Transcription Factor ; Insulin-Like Growth Factor I (67763-96-6)
    Language English
    Publishing date 2011-11
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 3029-6
    ISSN 1945-7197 ; 0021-972X
    ISSN (online) 1945-7197
    ISSN 0021-972X
    DOI 10.1210/jc.2011-1597
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: A novel GHR intronic variant, c.266+83G>T , activates a cryptic 5' splice site causing severe GHR deficiency and classical GH insensitivity syndrome.

    Feigerlova, Eva / Swinyard, Mike / Derr, Michael A / Farnsworth, Jeannie / Andrew, Shayne F / Rosenfeld, Ron G / Hwa, Vivian

    Hormone research in paediatrics

    2013  Volume 80, Issue 6, Page(s) 397–405

    Abstract: Background/aims: Mutations in the human growth hormone receptor gene (GHR) are the most common cause of growth hormone insensitivity (GHI) syndrome and insulin-like growth factor (IGF-1) deficiency. The extracellular domain of GHR (encoded by exons 2-7 ... ...

    Abstract Background/aims: Mutations in the human growth hormone receptor gene (GHR) are the most common cause of growth hormone insensitivity (GHI) syndrome and insulin-like growth factor (IGF-1) deficiency. The extracellular domain of GHR (encoded by exons 2-7 of the GHR gene) can be proteolytically cleaved to circulate as GH-binding protein (GHBP).
    Methods: We evaluated the cause of classical GHI (Laron) phenotypes in 3 siblings.
    Results: Two brothers (aged 16.5 and 14.9 years) and their half-brother (aged 11.3 years) presented with extreme short stature (height standard deviation score, SDS, of -7.05, -6.34 and -8.02, respectively). The parents were consanguineous and of normal stature. Serum GHBP levels of probands were undetectable and circulating IGF-1 and IGF-binding protein-3 were abnormally low, but GH concentrations were elevated. Molecular analysis of the GHR gene revealed homozygous deletion of exon 3, a common polymorphism, and a novel c.266+83G>T variant within intron 4 which generated a 5' donor splice site. Splicing events from this cryptic 5' donor site resulted in retention of 81 intronic nucleotides in the GHR mRNA. Long-term rhIGF-1 therapy combined with leuprolide depot increased height by +2 to +3 SDS.
    Conclusion: The c.266+83G>T is the second intronic GHR mutation identified that activates a cryptic 5' donor splice site. The abnormal splicing event led to early protein termination and undetectable serum GHBP concentrations. © 2013 S. Karger AG, Basel.
    MeSH term(s) Adolescent ; Base Sequence ; Child ; Humans ; Insulin-Like Growth Factor I/therapeutic use ; Introns/genetics ; Laron Syndrome/drug therapy ; Laron Syndrome/genetics ; Male ; Molecular Sequence Data ; Pedigree ; Polymorphism, Single Nucleotide ; RNA Splice Sites/genetics ; Receptors, Somatotropin/genetics ; Severity of Illness Index ; Siblings
    Chemical Substances RNA Splice Sites ; Receptors, Somatotropin ; Insulin-Like Growth Factor I (67763-96-6)
    Language English
    Publishing date 2013
    Publishing country Switzerland
    Document type Case Reports ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2537278-6
    ISSN 1663-2826 ; 1663-2818
    ISSN (online) 1663-2826
    ISSN 1663-2818
    DOI 10.1159/000355404
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  8. Article ; Online: Atypical GH insensitivity syndrome and severe insulin-like growth factor-I deficiency resulting from compound heterozygous mutations of the GH receptor, including a novel frameshift mutation affecting the intracellular domain.

    Aisenberg, Javier / Auyeung, Valerie / Pedro, Helio F / Sugalski, Rachel / Chartoff, Amy / Rothenberg, Rachel / Derr, Michael A / Hwa, Vivian / Rosenfeld, Ron G

    Hormone research in paediatrics

    2010  Volume 74, Issue 6, Page(s) 406–411

    Abstract: Background/aims: GH insensitivity and IGF deficiency may result from aberrations of the GH receptor (GHR). We describe a 4-year-old child with modest growth failure and normal serum concentrations of GH-binding protein (GHBP), but clinical evidence of ... ...

    Abstract Background/aims: GH insensitivity and IGF deficiency may result from aberrations of the GH receptor (GHR). We describe a 4-year-old child with modest growth failure and normal serum concentrations of GH-binding protein (GHBP), but clinical evidence of GH insensitivity.
    Method: Serum and DNA samples from the proband and his parents were analyzed.
    Results: The child had a height of -4 SD, elevated serum GH concentrations, abnormally low serum IGF-I and IGFBP-3 concentrations and normal GHBP concentrations. DNA analysis revealed compound heterozygosity for mutations of GHR, including a previously reported R211H mutation and a novel duplication of a nucleotide in exon 9 (899dupC), the latter resulting in a frameshift and a premature stop codon. Treatment with recombinant DNA-derived IGF-I resulted in growth acceleration.
    Conclusion: Mutations affecting the intracellular domain of the GHR can result in GH insensitivity and IGF deficiency, despite normal serum concentrations of GHBP. The presence of clinical and biochemical evidence of GH resistance is sufficient to consider the possibility of aberrations of the GHR, even in the presence of normal serum GHBP concentrations.
    MeSH term(s) Amino Acid Sequence ; Carrier Proteins/blood ; Child, Preschool ; DNA/chemistry ; DNA/genetics ; Female ; Frameshift Mutation ; Growth Disorders/blood ; Growth Disorders/drug therapy ; Growth Disorders/genetics ; Human Growth Hormone/blood ; Humans ; Insulin-Like Growth Factor I/deficiency ; Insulin-Like Growth Factor I/therapeutic use ; Male ; Molecular Sequence Data ; Point Mutation ; Polymerase Chain Reaction ; Receptors, Somatotropin/genetics ; Sequence Analysis, DNA
    Chemical Substances Carrier Proteins ; Receptors, Somatotropin ; somatotropin-binding protein ; Human Growth Hormone (12629-01-5) ; Insulin-Like Growth Factor I (67763-96-6) ; DNA (9007-49-2)
    Language English
    Publishing date 2010
    Publishing country Switzerland
    Document type Case Reports ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2537278-6
    ISSN 1663-2826 ; 1663-2818
    ISSN (online) 1663-2826
    ISSN 1663-2818
    DOI 10.1159/000314968
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  9. Article ; Online: Large-scale pooled next-generation sequencing of 1077 genes to identify genetic causes of short stature.

    Wang, Sophie R / Carmichael, Heather / Andrew, Shayne F / Miller, Timothy C / Moon, Jennifer E / Derr, Michael A / Hwa, Vivian / Hirschhorn, Joel N / Dauber, Andrew

    The Journal of clinical endocrinology and metabolism

    2013  Volume 98, Issue 8, Page(s) E1428–37

    Abstract: Context: The majority of patients presenting with short stature do not receive a definitive diagnosis. Advances in genetic sequencing allow for large-scale screening of candidate genes, potentially leading to genetic diagnoses.: Objectives: The ... ...

    Abstract Context: The majority of patients presenting with short stature do not receive a definitive diagnosis. Advances in genetic sequencing allow for large-scale screening of candidate genes, potentially leading to genetic diagnoses.
    Objectives: The purpose of this study was to discover genetic variants that contribute to short stature in a cohort of children with no known genetic etiology.
    Design: This was a prospective cohort study of subjects with short stature.
    Setting: The setting was a pediatric endocrinology and genetics clinics at an academic center.
    Patients: A total of 192 children with short stature with no defined genetic etiology and 192 individuals of normal stature from the Framingham Heart Study were studied.
    Intervention: Pooled targeted sequencing using next-generation DNA sequencing technology of the exons of 1077 candidate genes was performed.
    Main outcome measures: The numbers of rare nonsynonymous genetic variants found in case patients but not in control subjects, known pathogenic variants in case patients, and potentially pathogenic variants in IGF1R were determined.
    Results: We identified 4928 genetic variants in 1077 genes that were present in case patients but not in control subjects. Of those, 1349 variants were novel (898 nonsynonymous). False-positive rates from pooled sequencing were 4% to 5%, and the false-negative rate was 0.1% in regions covered well by sequencing. We identified 3 individuals with known pathogenic variants in PTPN11 causing undiagnosed Noonan syndrome. There were 9 rare potentially nonsynonymous variants in IGF1R, one of which is a novel, probably pathogenic, frameshift mutation. A previously reported pathogenic variant in IGF1R was present in a control subject.
    Conclusions: Large-scale sequencing efforts have the potential to rapidly identify genetic etiologies of short stature, but data interpretation is complex. Noonan syndrome may be an underdiagnosed cause of short stature.
    MeSH term(s) Adolescent ; Adult ; Body Height/genetics ; Child ; Child, Preschool ; Cohort Studies ; Female ; Genetic Variation ; Growth Disorders/genetics ; Human Growth Hormone/deficiency ; Humans ; Male ; Mutation ; Noonan Syndrome/genetics ; Osteochondrodysplasias/genetics ; Prospective Studies ; Protein Tyrosine Phosphatase, Non-Receptor Type 11/genetics ; Receptor, IGF Type 1/genetics ; Sequence Analysis, DNA ; Young Adult
    Chemical Substances Human Growth Hormone (12629-01-5) ; Receptor, IGF Type 1 (EC 2.7.10.1) ; PTPN11 protein, human (EC 3.1.3.48) ; Protein Tyrosine Phosphatase, Non-Receptor Type 11 (EC 3.1.3.48)
    Language English
    Publishing date 2013-06-14
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 3029-6
    ISSN 1945-7197 ; 0021-972X
    ISSN (online) 1945-7197
    ISSN 0021-972X
    DOI 10.1210/jc.2013-1534
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Familial short stature caused by haploinsufficiency of the insulin-like growth factor i receptor due to nonsense-mediated messenger ribonucleic acid decay.

    Fang, Peng / Schwartz, I David / Johnson, Betty D / Derr, Michael A / Roberts, Charles T / Hwa, Vivian / Rosenfeld, Ron G

    The Journal of clinical endocrinology and metabolism

    2009  Volume 94, Issue 5, Page(s) 1740–1747

    Abstract: Background: IGF-I, essential for normal human growth in utero and postnatally, mediates its effects through the IGF-I receptor (IGF1R), a widely expressed, cell surface tyrosine kinase receptor. Five cases of heterozygous mutations in the IGF1R gene ... ...

    Abstract Background: IGF-I, essential for normal human growth in utero and postnatally, mediates its effects through the IGF-I receptor (IGF1R), a widely expressed, cell surface tyrosine kinase receptor. Five cases of heterozygous mutations in the IGF1R gene have been identified in patients with varying degrees of intrauterine and postnatal growth retardation.
    Objective: The objective of the study was the analysis of the IGF1R gene in a short-statured patient and his affected family members.
    Patient: The male patient, with a height of -3.1 sd score (SDS; aged 12 yr), had normal circulating levels of GH binding protein, IGF-I, and IGF binding protein-3. His mother (-4.6 SDS), one of his siblings (-1.94 SDS), and several other maternal family members were also short statured.
    Results: The patient, his mother, and the short-statured sibling carry a novel heterozygous 19-nucleotide duplication within exon 18 of the IGF1R gene, which introduces a premature termination codon at codon 1106 of the IGF1R open reading frame on one allele. Analyses of the primary dermal fibroblasts derived from the patient and family members indicated that the IGF1R mRNA expressed from the mutant allele was degraded through the nonsense-mediated mRNA decay pathway, resulting in reduced amount of wild-type IGF1R protein and, subsequently, diminished activation of the IGF1R pathway.
    Conclusions: The mutation results in haploinsufficiency of IGF1R protein due to nonsense-mediated mRNA decay and is associated with familial short stature.
    MeSH term(s) Alleles ; Base Sequence ; Blotting, Western ; Body Height/genetics ; Carrier Proteins/blood ; Carrier Proteins/genetics ; Cells, Cultured ; Child ; Codon, Nonsense/genetics ; Codon, Nonsense/physiology ; DNA, Complementary/biosynthesis ; DNA, Complementary/genetics ; Exons/genetics ; Fetal Growth Retardation/genetics ; Fibroblasts/metabolism ; Growth Disorders/genetics ; Haplotypes ; Heterozygote ; Humans ; Insulin-Like Growth Factor Binding Protein 3/genetics ; Insulin-Like Growth Factor Binding Protein 3/metabolism ; Insulin-Like Growth Factor I/genetics ; Insulin-Like Growth Factor I/metabolism ; Male ; RNA, Messenger/genetics ; Receptor, IGF Type 1/genetics ; Receptor, IGF Type 1/physiology ; Recombinant Proteins/biosynthesis ; Recombinant Proteins/genetics
    Chemical Substances Carrier Proteins ; Codon, Nonsense ; DNA, Complementary ; Insulin-Like Growth Factor Binding Protein 3 ; RNA, Messenger ; Recombinant Proteins ; somatotropin-binding protein ; Insulin-Like Growth Factor I (67763-96-6) ; Receptor, IGF Type 1 (EC 2.7.10.1)
    Language English
    Publishing date 2009-05
    Publishing country United States
    Document type Case Reports ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 3029-6
    ISSN 1945-7197 ; 0021-972X
    ISSN (online) 1945-7197
    ISSN 0021-972X
    DOI 10.1210/jc.2008-1903
    Database MEDical Literature Analysis and Retrieval System OnLINE

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