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A Novel IVS2 -2A>T Splicing Mutation in the GH-1 Gene in Familial Isolated Growth Hormone Deficiency Type II in the Spectrum of Other Splicing Mutations in the Russian Population

Russian Academy of Medical Sciences, Department of Pediatrics, Endocrinology Research Center (O.V.F., V.A.P., I.I.D.), Moscow 117036; DNA-Diagnostics Laboratory (O.V.E., A.V.P.), Research Center for Medical Genetics, Moscow 115478; and Russian Academy of Sciences, Laboratory of Automatic DNA-Sequencing (A.B.P.), Engelgardt Institute of Molecular Biology, Moscow 119991, Russia

Address all correspondence and requests for reprints to: Olga V. Fofanova, Department of Pediatrics, Endocrinology Research Center, Russian Academy of Medical Sciences, 11 Dmitrija Uljanov Street, 117036 Moscow, Russia. E-mail: olga-vf{at}yandex.ru.

Isolated GH deficiency (IGHD) is characterized by genetic heterogeneity, both in familial and sporadic cases. To determine if this statement can be applied to the Russian population, we performed screening for mutations in the GH-1 gene in children living in Russia with IGHD. Twenty-eight children from 26 families with total IGHD were studied. DNA fragments, covering each of four (2–5) exons of GH-1 were amplified using PCR. Single-strand conformation polymorphism analysis followed by direct DNA sequencing identified five heterozygous mutations of splicing in intron 2, intron 3, and exon 4 of GH-1; three of them were not previously reported. We concentrated here on dominant-negative mutations causing IGHD type II, which were as follows: 1) A>T transversion of the second base of the 3'-acceptor splice site of intron 2 (IVS2 -2A>T); 2) T>C transition of the second base of the 5'-donor splice site of intron 3 (IVS3 +2T>C); 3) G>A transition of the first base of the 5'-donor splice site of intron 3 (IVS3 +1G>A). Our data indicate allelic heterogeneity of IGHD type II (IGHD II). However, all mutations in Russian IGHD II patients affect splicing, a striking difference from the mutation spectrum of other IGHD forms. The IVS2 -2A>T mutation is the first identified mutation in intron 2 of GH-1. The 5'-donor splice site of intron 3 of GH-1 is a mutational hot spot, and the IVS3 +1G>A mutation can be considered to be a common molecular defect in IGHD II in Russian patients.

This work was presented in part at the Pharmacia 29th International Symposium "Growth Hormone and Growth Factors in Endocrinology and Metabolism" (Marrakech, Morocco, April 2000); at the 39th Annual Meeting of the European Society for Paediatric Endocrinology, ESPE (Brussels, Belgium, 17–19 September, 2000); and at the International Congress of Endocrinology, ICE 2000 (Sydney, Australia, 29 October-2 November, 2000).

Abbreviations: BA, Bone age; CA, chronological age; fT₄, free T₄; HSDS, height SD score; HV, height velocity; IGHD, isolated GH deficiency; IGHD II, IGHD type II; ITT, insulin tolerance test; SSCP, single-strand conformation polymorphism.

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