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An Exon Splice Enhancer Mutation Causes Autosomal Dominant GH Deficiency

Department of Pediatrics, Vanderbilt University School of Medicine (C.T.M., M.A.P., J.A.P.), Nashville, Tennessee 37232-2578; and Department of Endocrinology, University Children’s Hospital, Inselspital (P.E.M.), Bern, Switzerland

Address all correspondence and requests for reprints to: Dr. John A. Phillips III, Division of Genetics, Vanderbilt University School of Medicine, DD-2205 Medical Center North, Nashville, Tennessee 37232-2578. E-mail: chanda.moseley{at}mcmail.vanderbilt.edu

Abstract

Familial isolated GH deficiency type II (IGHD II) is caused, in some cases, by heterogeneous IVS3 mutations that affect GH mRNA splicing. We report here our finding an AG transition of the fifth base of exon 3 (E3+ 5 AG) in affected individuals from an IGHD II family. This mutation disrupts a (GAA)_n exon splice enhancer (ESE) motif immediately following the weak IVS2 3' splice site. The mutation also destroys an MboII site used to demonstrate heterozygosity in all affected family members. To determine the effect of ESE mutations on GH mRNA processing, GH₃ cells were transfected with expression constructs containing the normal ESE, +5 AG, or other ESE mutations, and cDNAs derived from the resulting GH mRNAs were sequenced. All ESE mutations studied reduced activation of the IVS2 3' splice site and caused either partial E3 skipping, due to activation of an E3+ 45 cryptic 3' splice site, or complete E3 skipping. Partial or complete E3 skipping led to loss of the codons for amino acids 32–46 or 32–71, respectively, of the mature GH protein. Our data indicate that the E3+ 5 AG mutation causes IGHD II because it perturbs an ESE required for GH splicing.

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