Context: Undetectable circulating growth hormone-binding protein (GHBP) can be indicative of a GH receptor (GHR) defect and cause GH insensitivity (GHI) syndrome. Case Report: The proband, severely growth retarded from birth, had a height of 73 cm (–6 SDS) and weight of 10.5 kg (–2.5 SDS) at the age of 3.25 years; her consanguineous parents were normal statured. Basal serum GH measurement was high, >40 ng/ml, while serum insulin-like growth factor-I (IGF-I; 8.5 ng/ml; normal, 13–100), IGF-binding protein 3 (126 ng/ml; normal, 365–1,294), acid labile subunit (0.59 mg/l; normal, 5.6–16), and GHBP (120 pmol/l; normal, 431–1,892) concentrations were all markedly low. Recombinant IGF-I therapy improved height to –4.4 SDS after 2.5 years of treatment. Results:GHR gene analysis revealed a homozygous c.784G>C transversion, the last nucleotide of exon 7; the parents were heterozygous for the mutation. Evaluation of GHR mRNA indicated c.784G>C was not a missense mutation but induced exon 7 excision, leading to a frame shift and predicted early protein termination. Conclusion: A novel homozygous GHRc.784G>C mutation, identified in a GHI patient, induced functional loss of the native intron 7 donor splice site, demonstrating, for the first time, the importance of exonic nucleotides at exon-intron junctions for normal GHR splicing.

1.
Hwa V, Nadeau K, Wit JM, Rosenfeld RG: STAT5b deficiency: lessons from STAT5b gene mutations. Best Pract Res Clin Endocrinol Metab 2011;25:61–75.
2.
David A, Hwa V, Metherell LA, Netchine I, Camacho-Hubner C, Clark AJ, Rosenfeld RG, Savage MO: Evidence for a continuum of genetic, phenotypic, and biochemical abnormalities in children with growth hormone insensitivity. Endo Rev 2011;32:472–497.
3.
Laron Z, Pertzelan A, Mannheimer S: Genetic pituitary dwarfism with high serum concentation of growth hormone – a new inborn error of metabolism? Isr J Med Sci 1966;2:152–155.
4.
Berg MA, Guevara-Aguirre J, Rosenbloom AL, Rosenfeld RG, Francke U: Mutation creating a new splice site in the growth hormone receptro genes of 37 Ecuadorean patients with Laron syndrome. Hum Mutat 1992;1:24–32.
5.
Baumbach L, Schiavi A, Bartlett R, Perera E, Day J, Brown MR, Stein S, Eidson M, Parks JS, Cleveland W: Clinical, biochemical, and molecular investigations of a genetic isolate of growth hormone insensitivity (Laron’s syndrome). J Clin Endocrinol Metab 1997;82:444–451.
6.
Metherell LA, Akker SA, Munroe PB, Rose SJ, Caulfield M, Savage MO, Chew SL, Clark AJ: Pseudoexon activation as a novel mechanism for disease resulting in atypical growth-hormone insensitivity. Am J Hum Genet 2001;69:641–646.
7.
David A, Miraki-Moud F, Shaw NJ, Savage MO, Clark AJ, Metherell LA: Identification and characterisation of a novel GHR defect disrupting the polypyrimidine tract and resulting in GH insensitivity. Eur J Endocrinol 2010;162:37–42.
8.
Kofoed EM, Hwa V, Little B, Woods KA, Buckway CK, Tsubaki J, Pratt KL, Bezrodnik L, Jasper H, Tepper A, Heinrich J, Rosenfeld RG: Growth-hormone insensitivity (GHI) associated with a STAT-5b mutation. N Engl J Med 2003;349:1139–1147.
9.
Hwa V, Little B, Kofoed EM, Rosenfeld RG: Transcriptional regulation of insulin-like growth factor-I (IGF-I) by interferon-gamma (IFN-γ) requires Stat-5b. J Biol Chem 2004;279:2728–2736.
10.
Enberg B, Luthman H, Segnestam K, Ritzén EM, Sundström M, Norstedt G: Characterisation of novel missense mutations in the GH receptor gene causing severe growth retardation. Eur J Endocrinol 2000;143:71–76.
11.
Hwa V, Little B, Adiyaman P, Kofoed EM, Pratt KL, Ocal G, Berberoglu M, Rosenfeld RG: Severe growth hormone insensivity resulting from total absence of signal transducer and activator of transcription 5b. J Clin Endocrinol Metab 2005;90:4260–4266.
12.
Ayling RM, Ross R, Towner P, Von Laue S, Finidori J, Moutoussamy S, Buchanan CR, Clayton PE, Norman MR: A dominant-negative mutation of the growth hormone receptor causes familial short stature. Nat Genet 1997;16:13–14.
13.
Iida K, Takahashi Y, Kaji H, Nose O, Okimura Y, Abe H, Chihara K: Growth hormone (GH) insensitivity syndrome with high serum GH-binding protein levels caused by a heterozygous splice site mutation of the GH receptor gene producing a lack of intracellular domain. J Clin Endocrinol Metab 1998;83:531–537.
14.
Derr MA, Aisenberg J, Fang P, Tenenbaum-Rakover Y, Rosenfeld RG, Hwa V: The growth hormone receptor (GHR) c.899dupC mutation functions as a dominant negative: insights into the pathophysiology of intracellular GHR defects. J Clin Endocrinol Metab 2011;96:E1896–E1904.
15.
Krawczak M, Thomas NST, Hendrieser B, Mort M, Wittig M, Hampe J, Cooper DN: Single base-pair substitutions in exon-intron junctions of human genes: nature, distribution, and consequences for mRNA splicing. Hum Mutat 2007;28:150–158.
16.
Amselem S, Duquesnoy P, Duriez B, Dastot F, Sobrier M-L, Valleix S, Goossens M: Spectrum of growth hormone receptor mutations and associated haplotypes in Laron syndrome. Hum Mol Genet 1993;2:355–359.
17.
Sterne-Weiler T, Howard J, Mort M, Cooper DN, Sanford JR: Loss of exon identity is a common mechanism of human inherited disease. Genome Res 2011;21:1563–1571.
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