Extreme Elevation of Serum Growth Hormone-Binding Protein Concentrations Resulting from a Novel Heterozygous Splice Site Mutation of the Growth Hormone Receptor Gene

Aalbers, Anna M.; Chin, Daisy; Pratt, Katherine L.; Little, Brian M.; Frank, Stuart J.; Hwa, Vivian; Rosenfeld, Ron G.

doi:10.1159/000208801

Cited by 16 publications

(23 citation statements)

References 64 publications

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“…Further support for this hypothesis is the finding of heterozygous GHR gene mutations in about 5% of ISS children [3,4,5,6,7]. Although most of the heterozygous GHR gene mutations previously reported have not been fully characterized at a functional level, more recently partial GH insensitivity has been demonstrated in patients with heterozygous GHR gene defects causing either dominant negative effects (splicing defects causing exon 8 skipping) [40] or a premature stop codon resulting in nonsense-mediated mRNA decay [41]. …”

Section: Discussionmentioning

confidence: 99%

Heterozygous IGFALS Gene Variants in Idiopathic Short Stature and Normal Children: Impact on Height and the IGF System

et al. 2013

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Background: In acid-labile subunit (ALS)-deficient families, heterozygous carriers of IGFALS gene mutations are frequently shorter than their wild-type relatives, suggesting that IGFALS haploinsufficiency could result in short stature. We have characterized IGFALS gene variants in idiopathic short stature (ISS) and in normal children, determining their impact on height and the IGF system. Patients and Methods: In 188 normal and 79 ISS children levels of IGF-1, IGFBP-3, ALS, ternary complex formation (TCF) and IGFALS gene sequence were determined. Results: In sum, 9 nonsynonymous or frameshift IGFALS variants (E35Gfs*17, G83S, L97F, R277H, P287L, A330D, R493H, A546V and R548W) were found in 10 ISS children and 6 variants (G170S, V239M, N276S, R277H, G506R and R548W) were found in 7 normal children. If ISS children were classified according to the ability for TCF enhanced by the addition of rhIGFBP-3 (TCF+), carriers of pathogenic IGFALS gene variants were shorter and presented lower levels of IGF-1, IGFBP-3 and ALS in comparison to carriers of benign variants. In ISS families, subjects carrying pathogenic variants were shorter and presented lower IGF-1, IGFBP-3 and ALS levels than noncarriers. Conclusions: These findings suggest that heterozygous IGFALS gene variants could be responsible for short stature in a subset of ISS children with diminished levels of IGF-1, IGFBP-3 and ALS.

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Section: Discussionmentioning

confidence: 99%

Heterozygous IGFALS Gene Variants in Idiopathic Short Stature and Normal Children: Impact on Height and the IGF System

et al. 2013

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“…The variability of clinical phenotypes (GHD, idiopathic short stature (ISS) and constitutional delay of growth and puberty (CDGP)) and incomplete segregation of the mutations with the phenotype still cast doubt on the role of GHSR mutations in causing short stature, although functional studies do suggest that GHSR mutations may decrease GH secretion (40,41,42), implying that GHSR mutations may GHI and decreased expression or biologic activity of IGF1or IGF2 Table 2 shows the various syndromes presenting with insensitivity to GH or IGF1. The first discovered cause of GHI was Laron syndrome, usually caused by a homozygous mutation of the gene encoding the GH receptor (GHR) (43,44,45 (48,49,50) or by heterozygous GHR mutations causing a dominant negative effect (51,52,53). In 2003 the first patient with a homozygous lossof-function mutation of the gene encoding the main component of the intracellular GH signalling pathway (STAT5B) was found (54), and since then ten patients have been reported in seven families (55).…”

Section: Gh Deficiencymentioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature

Wit

Oostdijk

Losekoot

et al. 2016

European Journal of Endocrinology

148

132

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The fast technological development, particularly single nucleotide polymorphism array, array-comparative genomic hybridization, and whole exome sequencing, has led to the discovery of many novel genetic causes of growth failure. In this review we discuss a selection of these, according to a diagnostic classification centred on the epiphyseal growth plate. We successively discuss disorders in hormone signalling, paracrine factors, matrix molecules, intracellular pathways, and fundamental cellular processes, followed by chromosomal aberrations including copy number variants (CNVs) and imprinting disorders associated with short stature. Many novel causes of GH deficiency (GHD) as part of combined pituitary hormone deficiency have been uncovered. The most frequent genetic causes of isolated GHD are GH1 and GHRHR defects, but several novel causes have recently been found, such as GHSR, RNPC3, and IFT172 mutations. Besides well-defined causes of GH insensitivity (GHR, STAT5B, IGFALS, IGF1 defects), disorders of NFkB signalling, STAT3 and IGF2 have recently been discovered. Heterozygous IGF1R defects are a relatively frequent cause of prenatal and postnatal growth retardation. TRHA mutations cause a syndromic form of short stature with elevated T 3 /T 4 ratio. Disorders of signalling of various paracrine factors (FGFs, BMPs, WNTs, PTHrP/IHH, and CNP/NPR2) or genetic defects affecting cartilage extracellular matrix usually cause disproportionate short stature. Heterozygous NPR2 or SHOX defects may be found in w3% of short children, and also rasopathies (e.g., Noonan syndrome) can be found in children without clear syndromic appearance. Numerous other syndromes associated with short stature are caused by genetic defects in fundamental cellular processes, chromosomal abnormalities, CNVs, and imprinting disorders.

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“…Not surprisingly, ~90% of GHR mutations identified to date localize to this domain [10]. In contrast, only a handful of mutations have been identified in the GHR intracellular domain and none in the TM, although four splicing variants that lead to loss of the entire TM and supraphysiological levels of serum GHBP have been reported [16] (fig. 2a).…”

Section: Ghr Mutations Are Associated With a Range Of Phenotypesmentioning

confidence: 99%

IGF-I in Human Growth: Lessons from Defects in the GH-IGF-I Axis

Hwa¹,

Peng²,

Derr³

et al. 2013

Nestlé Nutrition Institute Workshop Series

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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.

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Extreme Elevation of Serum Growth Hormone-Binding Protein Concentrations Resulting from a Novel Heterozygous Splice Site Mutation of the Growth Hormone Receptor Gene

Cited by 16 publications

References 64 publications

Heterozygous <b><i>IGFALS</i></b> Gene Variants in Idiopathic Short Stature and Normal Children: Impact on Height and the IGF System

Heterozygous <b><i>IGFALS</i></b> Gene Variants in Idiopathic Short Stature and Normal Children: Impact on Height and the IGF System

MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature

IGF-I in Human Growth: Lessons from Defects in the GH-IGF-I Axis

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