Genes for Human Growth HormoneLike Proteins
Page 829 CLINICAL CORRELATION 19.5 Prenatal Diagnosis of Thalassemia If a fetus is suspected of being thalassemic because of its genetic background, recombinant DNA techniques can be used to determine if one or more globin genes are missing from its genome. Fetal DNA can easily be obtained (in relatively small quantities) from amniotic fluid cells aspirated early during the second trimester of pregnancy. Regions of interest are amplified from the fetal DNA by polymerase chain reactions and digested with restriction enzymes that divide the globin genes among restriction fragments of several hundred to 2000 base pairs. These fragments are separated by electrophoresis through an agarose gel and hybridized with radioactive cDNA for a and/or b globin using the Southern blot technique (see p. 774). If one or more globin genes are missing, the corresponding restriction fragment will not be detected or its hybridization to the radioactive cDNA probe will be reduced (in the case when only one of two diploid genes is absent). Benz, E. J. The hemoglobinopathies. In: W. N. Kelly (Ed.), Textbook of Internal Medicine. Philadelphia: Lippincott, 1989, pp. 1423–1432. product is a composite of the and b sequence, but the actual fusion junction is different. Another fusion b like globin is Hb Kenya. This deletion results in a gene product that contains the Nterminal sequence of the gglobin gene and the Cterminal sequence of the b globin gene. Still another series of deletions has been found in which both the and b globin genes are removed, causing HPFH (hereditary persistence of fetal hemoglobin). Frequently, there are no clinical symptoms of this condition because fetal hemoglobin ( 2 2) continues to be synthesized after the time at which gglobin gene expression is normally turned off (see Clin. Corr. 19.5.) 19.11— Genes for Human Growth HormoneLike Proteins Human growth hormone (hGH, also called somatotropin) is a polypeptide of 191 amino acids. A larger precursor is synthesized in the somatotrophs of the anterior pituitary, and the mature form is secreted into the circulatory system. Growth hormone induces liver (and perhaps other) cells to produce other hormones called somatomedins, which are insulinlike growth factors that stimulate proliferation of mesodermal tissues such as bone, cartilage, and muscle. Infants with a deficiency in growth hormone become dwarfs, whereas those who produce too much become giants. A closely related protein of 191 amino acids, having 85% homology with growth hormone, is human chorionic somatomammotropin (hCS, also called placental lactogen) synthesized in the placenta. The complete role of this hormone in normal fetal–maternal physiology is still unclear, but it participates in placental growth and contributes to mammary gland preparation for lactation during pregnancy. The hormones hGH and hCS are examples of two very similar proteins that serve different biological functions and are synthesized in different tissues. It is to be expected that their genes also are closely related but expressed in a tissuespecific fashion. The genes for hGH and hCS are very similar and occur in the same region of chromosome 17 (Figure 19.26). Five related genes comprise the human growth hormone gene family. They occur over a distance of about 55 kb and share a common structure of five exons and four introns, with the exon–intron boundaries always in the same locations. Alu repetitive sequences occur between some of the genes, as in the globin gene clusters. The order of the genes is 5 hGHN y hCSL, hCSA, hGHV, hCSB 3¢. The first gene in this cluster, hGHN, is expressed in the anterior Figure 19.26 Organization of human growth hormone (hGH) gene family. The five structural genes of this family occur as a linear array over about 55 kb on the long arm of chromosome 17. Two genes (hGHN and hGHV) code for growth hormone, two genes code for the closely related human chorionic somatomammotropin (hCSA and hCSB), and one gene appears to be a pseudogene ( hCSL). Only hGHN is expressed in the pituitary; other genes are expressed in the placenta. The order of the genes in the array (red boxes) is 5 hGHN, hCSL, hCSA, hGHV, hCSB 3 , and all are transcribed in the same direction. Each gene has the same basic structure of five exons and four introns (not shown). Redrawn from Chen, E. Y., Liao, Y. C., Smith, D. H., BarreraSaldana, H. A. et al. Genomics 2:479, 1989.