Isolated GH Deficiency with Dominant Inheritance: New Mutations, New Insights

Binder, Gerhard; Keller, Elizabeth B.; Mix, M.; Massa, Guy; Stokvis-Brantsma, Wilhelmina H.; Wit, Jan M.; Ranke, Michael B.

doi:10.1210/jcem.86.8.7757

Cited by 62 publications

(23 citation statements)

References 24 publications

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“…These include the substitution of leucine for proline (P89L), histidine for arginine (R183H) and phenylalanine for valine (V110F) respectively (13 -16). Severe short stature (,24.5 standard deviation score (SDS)) is not invariably present in all affected individuals (15). Binder et al have hypothesized that children with splice site mutations may be younger and shorter at diagnosis than their counterparts with missense mutations (15).…”

Section: Introductionmentioning

confidence: 99%

Variability of isolated autosomal dominant GH deficiency (IGHD II): impact of the P89L GH mutation on clinical follow-up and GH secretion

Salemi

Yousefi²,

Baltensperger³

et al. 2005

eur j endocrinol

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Objective: Four distinct familial types of isolated GH deficiency (IGHD) are classified, of which type II, IGHD II, is the autosomal dominant inherited form. Based on clinical data, it became evident that there is a wide variability in phenotype among the various GH-1 gene alterations leading to the disorder. As subjects suffering from IGHD II caused by the specific missense mutated P89L GH (C6129T) have never been reported in detail, the aim was to analyse the impact of this mutated GH form on its clinical follow-up as well as to study its effect at the cellular level in comparison with the most common missense mutation R183H GH (G6664A). Methods: Twelve subjects belonging to four families presenting with P89L GH were clinically compared with 17 subjects from 5 families with the R183H GH missense mutation. Further, co-localization of the wild-type (wt-type) and mutant GH forms was studied in AtT-20 cells, mouse pituitary gland, applying quantitative confocal microscopy analysis. Using immunofluorescent techniques, cells were double stained for GH and one of the following organelles: endoplasmic reticulum (antiGrp94), Golgi (anti-bCOP) and secretory granules (anti-Rab3a). In addition, GH secretion and cell viability was analysed in detail. Results: Importantly, as well as growth hormone deficiency, eight out of twelve subjects with the P89L mutated GH form developed other endocrine deficits and the pituitary gland became smaller over time (P , 0.05). At the cellular level, quantitative analysis of the variable mutants expressed in AtT-20 cells revealed a different extent of co-localization, different effects on GH secretion, and, therefore, a different impact on the secretory pathway which might be caused by different folding or aggregation problems necessary for sorting, packaging and/or secretion through the regulated secretory pathway. Conclusions: Our results show that specific and detailed analyses of the different mutations identified in IGHD II may shed light on the different mechanisms of secretory pathophysiology, and may provide a better explanation of the range of clinical features associated with GH missense isoforms. Importantly, the findings in patients with P89L GH extend beyond classical IGHD and stress the need for continued clinical vigilance in IGHD II patients for the development of other hormonal deficiencies.European Journal of Endocrinology 153 791-802

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Section: Introductionmentioning

confidence: 99%

Variability of isolated autosomal dominant GH deficiency (IGHD II): impact of the P89L GH mutation on clinical follow-up and GH secretion

Salemi

Yousefi²,

Baltensperger³

et al. 2005

eur j endocrinol

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“…The aim of this study was to define the specific pituitary gland morphology assessed by MRI of patients with familial IGHD type II due to GH-1 gene mutations (9) and to compare these findings with the gland morphology found in patients with idiopathic IGHD who exhibited a similar biochemical and clinical severity. In addition, perinatal history was studied in both groups in order to re-examine the perinatal trauma hypothesis as a cause for severe IGHD (8).…”

Section: Introductionmentioning

confidence: 99%

Isolated GH deficiency (IGHD) type II: imaging of the pituitary gland by magnetic resonance reveals characteristic differences in comparison with severe IGHD of unknown origin

Binder

Nagel

Ranke

et al. 2002

European Journal of Endocrinology

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Objective: To determine the specific morphology of the pituitary gland in children with severe isolated GH deficiency due to GH-1 gene mutations (IGHD type II). Design: The pituitary gland morphology in magnetic resonance imaging (MRI) of children with IGHD type II was analyzed and compared with the findings in a group of children with comparably severe IGHD of unknown origin. In addition, the birth histories of both groups were studied. Subjects: Thirteen children with IGHD type II were diagnosed in seven European children's hospitals and they carried a corresponding GH-1 gene mutation. For comparison, we selected from a group of 66 MRI-studied GH-insufficient subjects diagnosed in our clinic, all children with severe IGHD (all GH peaks , 4 mg/l) who had no GH-1 gene mutation, no first-grade relative with IGHD and no septo-optic dysplasia. Methods: Sagittal and coronal images of the brain were analyzed for the presence of any malformation of the pituitary gland and the intracranium. The height of each adenohypophysis was measured in a strict midline sagittal image for quantification of the gland's size. In addition, patients' files were reviewed for birth trauma or breech delivery. Results: Normal MRI morphology of the pituitary gland was observed in all patients of the familial IGHD type II group ðP , 0:003Þ in which, however, five of thirteen patients (38%) exhibited a mild hypoplasia of their gland (mean sagittal adenohypophysial height 21:0^0:03 SD score (SDS)). In contrast, the pituitary gland in the idiopathic group showed a definitive malformation with hypoplasia of pituitary stalk and adenohypophysis in all cases, while ectopia of the neurohypophysis was present in nine of the ten cases. The adenohypophysis was significantly smaller in the idiopathic group (mean sagittal adenohypophysial height 23:2^0:3 SDS) ðP , 0:0001Þ: All thirteen birth histories in the familial group (IGHD type II) were unremarkable while, in the idiopathic group, three of eight available birth histories recorded a breech delivery or traumatic birth (37.5%) ðP , 0:05Þ: Conclusions: This study shows for the first time that MRI pituitary morphology may correlate with the etiology of severe IGHD: normal morphology suggests the presence of GH-1 gene mutations, while severe hypoplasia with malformation have other causes which might include so far unknown genetic defects as well as traumatic insults.

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“…Furthermore, since the previously described p.D116A-GH harboring a missense mutation within the GH receptor-binding site 2 has a 5.7-fold lower affinity to the GH receptor than the WT-GH (15), this would argue for a functional importance of the D116 residue and implicate a similar functional alteration of the p.D116E-GH. In addition, although GH1 missense mutations reported to date are relatively rare (16), GH missense MTs, including those within or near the GH receptor binding site 2, frequently have a reduced or altered biological activity (2,4,(17)(18)(19)(20)(21).…”

Section: Discussionmentioning

confidence: 99%

An immunologically anomalous but considerably bioactive GH produced by a novel GH1 mutation (p.D116E)

Dateki

Hizukuri²,

Tanaka³

et al. 2009

European Journal of Endocrinology

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Contex: Although GH values measured by an immunoassay usually reflect GH bioactivities, discrepancy exists between immunoactivity and bioactivity in a rare condition known as 'bioinactive GH'. Objective: To report an immunologically anomalous but considerably bioactive GH. Methods: We performed mutational and functional analyses of GH1 in a 7-year-old Japanese boy with short stature (K3.0 S.D.) in whom serum GH values measured with a Tosoh immunoassay kit were all undetectable in three provocation tests, whereas urine GH value measured with a Hitachi immunoassay kit was within the normal range. Serum IGF-1 was at a low-normal range, and IGF-binding protein-3 was below the normal range. Results: Mutation analysis showed a missense GH produced by a novel GH1 mutation (p.D116E) of paternal origin and a frameshift mutation (p.Q68fsX106) of maternal origin. Genotype-phenotype correlations in this family and in vitro functional studies indicated that the p.D116E-GH was immeasurable with the Tosoh kit but was measurable, though maybe not precise, with a Daiichi kit, and had a reduced in vivo bioactivity. The p.Q68fsX106 yielded no GH protein. Conclusions:The results suggest that the p.D116E affects the GH epitope primarily recognized by the Tosoh kit but not by the Hitachi or the Daiichi kits, thereby producing an immunologically anomalous but considerably bioactive GH. The presence of such a hormone discordant for immunoactivity and bioactivity should be kept in mind, to allow for an appropriate assessment of endocrine data.

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Isolated GH Deficiency with Dominant Inheritance: New Mutations, New Insights

Cited by 62 publications

References 24 publications

Variability of isolated autosomal dominant GH deficiency (IGHD II): impact of the P89L GH mutation on clinical follow-up and GH secretion

Variability of isolated autosomal dominant GH deficiency (IGHD II): impact of the P89L GH mutation on clinical follow-up and GH secretion

Isolated GH deficiency (IGHD) type II: imaging of the pituitary gland by magnetic resonance reveals characteristic differences in comparison with severe IGHD of unknown origin

An immunologically anomalous but considerably bioactive GH produced by a novel GH1 mutation (p.D116E)

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