A Gene Deletion is Responsible for Absence of Human Chorionic Somatomammotropin

Wurzel, John; Parks, John S.; Herd, J. E.; Nielsen, Pernille

doi:10.1089/dna.1.1982.1.251

Cited by 88 publications

(52 citation statements)

References 18 publications

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“…The relative positions of the six different polymorphic sites with respect to the genes in the hGH cluster are shown in Fig. 1 (7,10,11 RFLPs, the structural locus adjacent to the polymorphic restriction site was determined by digesting large genomic HindIII fragments with each endonuclease (7). The distance of the polymorphic site from its adjacent locus was deduced by comparing the fragment lengths observed with the DNA sequence of each hGH or hCS locus and the physical map of the cluster (refs.…”

Section: Methodsmentioning

confidence: 99%

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Patterns of polymorphism and linkage disequilibrium suggest independent origins of the human growth hormone gene cluster.

Chakravarti¹,

Phillips²,

Mellits³

et al. 1984

Proc. Natl. Acad. Sci. U.S.A.

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Six restriction fragment length polymorphisms (RFLPs) detected in the human growth hormone-human chorionic somatomammotropin (hGH-hCS) gene duster were studied in Mediterraneans, Northern Europeans, and American Blacks; the polymorphisms showed that, on the average, one of 500 bases in this cluster is variant. Haplotypes constructed for four of these RFLPs display strong nonrandom associations. However, the strongest associations were between RFLPs that are in homologous DNAs rather than between the physically closest RFLPs. From this and other evidence we argue that duplication of an ancestral hCS gene occurred at least twice, the second event being relatively recent.

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Section: Methodsmentioning

confidence: 99%

“…The second duplication event leading to hCS-A is relatively recent. This implies that hCS deficiency due to absent hCS genes (10,11) may not be due to hCS gene deletions per se but rather represents the nonduplicated ancestral unit.…”

mentioning

confidence: 99%

Patterns of polymorphism and linkage disequilibrium suggest independent origins of the human growth hormone gene cluster.

Chakravarti¹,

Phillips²,

Mellits³

et al. 1984

Proc. Natl. Acad. Sci. U.S.A.

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“…Although production of PL is massive, appears early in human pregnan cy, and increases in parallel with placental weight, its absence in humans does not seem to be detrimental to growth. Infants with complete deletions of the PL genes have normal prenatal growth, despite extremely low levels of this hormone in the maternal circulation (31,32). Although it has both lactogen ic and somatogenic properties (33), it is not potent as a postnatal GH (34).…”

Section: Hrh [mentioning

confidence: 99%

Ontogeny of Growth Hormone Releasing Hormone and Insulin-Like Growth Factors-I and-II Messenger RNA in Rat Placenta

1991

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“…However, Goossens et al (8) have reported that the DNA from one IGHD 1A patient was homologous for a double deletion in which the only component of the GH gene cluster retained was the chorionic somatomammotropin pseudogene CSHPL. Homozygosity for deletions encompassing the genes for CSHJ or CSHI-GH2-CSH2 has also been reported in phenotypically normal individuals (9,10).…”

mentioning

confidence: 96%

“…The presence of highly homologous DNA sequences in this cluster would predispose to the misalignment under- lying both mechanisms. Because of the homology present throughout the GH gene cluster it is likely that the molecular basis of CSHI or CSHJ-GH2-CSH2 gene deletions may have resulted from similar mechanisms (8)(9)(10). DNA sequencing of the Mst II junction fragments from the eight subjects with 6.7-kb GHJ gene deletions should identify the precise breakpoints that will clarify the role of Alu and/or other DNA repeats in GHJ gene deletions.…”

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confidence: 99%

Molecular basis of human growth hormone gene deletions.

Phillips¹,

Chen²,

Seeburg

1988

Proc. Natl. Acad. Sci. U.S.A.

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Crossover sites resulting from unequal recombination within the human growth hormone (GH) gene cluster that cause GH1 gene deletions and isolated GH deficiency type 1A were localized in nine patients. In eight unrelated subjects homozygous for 6.7-kilobase (kb) deletions, the breakpoints are within two blocks of highly homologous DNA sequences that lie 5' and 3' to the GHI gene. In seven of these eight cases, the breakpoints map within a 1250-base-pair (bp) region composed of 300-bp Alu sequences of 86% homology and flanking non-Alu sequences that are 600 and 300 bp in length and are of 96% and 88% homology, respectively. In the eighth patient, the breakpoints are 5' to these Alu repeats and are most likely within a 700-bp region of 96% homologous DNA sequences. In the ninth patient homozygous for a 7.6-kb deletion, the breakpoints are contained within a 29-bp perfect repeat lying 5' to GH1 and the human chorionic somatomammotropin pseudogene (CSHPI). Together, these results indicate that the presence of highly homologous DNA sequences flanking GHI predispose to recurrent unequal recombinational events presumably through chromosomal misalignment.Familial isolated growth hormone deficiency (IGHD) type 1A is characterized by complete absence of growth hormone (GH) frequently but not always associated with immune intolerance to exogenous GH (1-3). This disorder has an autosomal recessive mode of inheritance and affected individuals are homozygous for deletion of the DNA encompassing the structural gene for growth hormone (GHI). GH1 is normally present at the 5' end of the 48-kilobase (kb) human GH gene cluster, which 5' -> 3' contains GHJ, CSHPI, CSHI, GH2, and CSH2. These genes map to chromosome 17q22-24 and retain 92-98% homology in their immediate flanking, intervening, and coding sequences (4-6). Although heterogeneity exists with regard to the sizes of the deletions, most (8/10) of those independently ascertained and characterized in our laboratory are =6.7 kb in length, whereas some (2/10) are slightly larger, spanning 7.6 kb (7). Only the GHJ locus was deleted in each and the remaining components of the cluster appeared intact. However, Goossens et al. (8) have reported that the DNA from one IGHD 1A patient was homologous for a double deletion in which the only component of the GH gene cluster retained was the chorionic somatomammotropin pseudogene CSHPL. Homozygosity for deletions encompassing the genes for CSHJ or CSHI-GH2-CSH2 has also been reported in phenotypically normal individuals (9, 10).We have previously reported that differences observed in restriction fragment length polymorphisms (RFLPs) flanking remaining components of the GH gene cluster suggest that most deletions resulted from independent deletion events (7 Restriction Endonuclease Analysis. High molecular weight nuclear DNA was isolated as described (22) from peripheral blood samples (10-20 ml) obtained from patients with IGHD type 1A and their relatives. Aliquots (5 pug) of DNA were digested with various restriction endonucleases...

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A Gene Deletion is Responsible for Absence of Human Chorionic Somatomammotropin

Cited by 88 publications

References 18 publications

Patterns of polymorphism and linkage disequilibrium suggest independent origins of the human growth hormone gene cluster.

Patterns of polymorphism and linkage disequilibrium suggest independent origins of the human growth hormone gene cluster.

Ontogeny of Growth Hormone Releasing Hormone and Insulin-Like Growth Factors-I and-II Messenger RNA in Rat Placenta

Molecular basis of human growth hormone gene deletions.

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