Diverse deletions in the growth hormone receptor gene cause growth hormoneinsensitivity syndrome

Growth hormone insensitivity syndrome (GHIS; also known as Laron syndrome), is characterized by severe postnatal growth failure and normal growth horm one. The syndrome is frequently caused by point mutations in the growth hor mone receptor gene (GHR). Here we report five families with GHIS and partia l deletions of the GHR gene. The deletion breakpoints were sequenced and PC R-based diagnostic tests were developed. In a Cambodian family, a novel del etion removed part of exon 5 and 1.2 kb of the preceding intron. The deleti on occurred by recombination within four identical nucleotides. In the muta nt transcript, skipping of the truncated exon 5 leads to a frameshift and p remature termination codon (PTC), A previously reported discontinuous delet ion of GHR exons 3, 5, and 6 was identified in three Oriental Jewish famili es. An unaffected individual was heterozygous for the exon 5 and 6 deletion , but homozygously deleted for exon 3 suggesting that the exon 3 deletion i s a polymorphism. The pathogenic deletion of exons 5 and 6 spans about 7.5 kb. Sequence analysis of the breakpoints revealed an imperfect junction bet ween introns 4 and 6, with a four basepair insertion. A novel deletion of 1 3 nucleotides within exon 9 was identified in a Caucasian girl with GHIS wh o carries the I153T missense mutation on her other allele, The exon 9 delet ion leads to a frameshift and PTC, The predicted protein retains the transm embrane domain and a short cytoplasmic tail. Four family members in three g enerations were carriers of this deletion, but only two of them were below normal for height, suggesting that this mutation by itself does not act as a dominant negative, as was reported for two other GHR mutations which lead to truncation of the intracellular domain. Hum Mutat 16:323-333, 2000, (C) 2000 Wiley-Liss, Inc.