Showing papers in "Nature Genetics in 1993"
TL;DR: The computer program BLASTX performed conceptual translation of a nucleotide query sequence followed by a protein database search in one programmatic step and was characterized as appropriate for use in moderate and large scale sequencing projects at the earliest opportunity, when the data are most prone to containing errors.
Abstract: Sequence similarity between a translated nucleotide sequence and a known biological protein can provide strong evidence for the presence of a homologous coding region, even between distantly related genes. The computer program BLASTX performed conceptual translation of a nucleotide query sequence followed by a protein database search in one programmatic step. We characterized the sensitivity of BLASTX recognition to the presence of substitution, insertion and deletion errors in the query sequence and to sequence divergence. Reading frames were reliably identified in the presence of 1% query errors, a rate that is typical for primary sequence data. BLASTX is appropriate for use in moderate and large scale sequencing projects at the earliest opportunity, when the data are most prone to containing errors.
1,798 citations
TL;DR: It is shown that this sequence forms part of a P–type ATPase gene (referred to here as Wc1) that is very similar to MNK, with six putative metal binding regions similar to those found in prokaryotic heavy metal transporters.
Abstract: Wilson disease (WD) is an autosomal recessive disorder of copper transport, resulting in copper accumulation and toxicity to the liver and brain. The gene (WD) has been mapped to chromosome 13 q14.3. On yeast artificial chromosomes from this region we have identified a sequence, similar to that coding for the proposed copper binding regions of the putative ATPase gene (MNK) defective in Menkes disease. We show that this sequence forms part of a P-type ATPase gene (referred to here as Wc1) that is very similar to MNK, with six putative metal binding regions similar to those found in prokaryotic heavy metal transporters. The gene, expressed in liver and kidney, lies within a 300 kb region likely to include the WD locus. Two WD patients were found to be homozygous for a seven base deletion within the coding region of Wc1. Wc1 is proposed as the gene for WD.
1,798 citations
TL;DR: There is a direct correlation between the size of the (CAG)n repeat expansion and the age–of–onset of SCA1, with larger alleles occurring in juvenile cases.
Abstract: Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant disorder characterized by neurodegeneration of the cerebellum, spinal cord and brainstem. A 1.2-Megabase stretch of DNA from the short arm of chromosome 6 containing the SCA1 locus was isolated in a yeast artificial chromosome contig and subcloned into cosmids. A highly polymorphic CAG repeat was identified in this region and was found to be unstable and expanded in individuals with SCA1. There is a direct correlation between the size of the (CAG)n repeat expansion and the age-of-onset of SCA1, with larger alleles occurring in juvenile cases. We also show that the repeat is present in a 10 kilobase mRNA transcript. SCA1 is therefore the fifth genetic disorder to display a mutational mechanism involving an unstable trinucleotide repeat.
1,586 citations
1,373 citations
TL;DR: A candidate gene (Mc1) for Menkes disease is isolated and qualitative or quantitative abnormalities in the mRNA in sixteen of twenty–one Menkes patients are found and predicted to be a P–type cation–transporting ATPase.
Abstract: Menkes disease is an X-linked disorder of copper transport characterized by progressive neurological degeneration and death in early childhood. We have isolated a candidate gene (Mc1) for Menkes disease and find qualitative or quantitative abnormalities in the mRNA in sixteen of twenty-one Menkes patients. Four patients lacking Mc1RNA showed rearrangements of the Menkes gene. The gene codes for a 1,500 amino acid protein, predicted to be a P-type cation-transporting ATPase. The gene product is most similar to a bacterial copper-transporting ATPase and additionally contains six putative metal-binding motifs at the N-terminus. The gene is transcribed in all cell types tested except liver, consistent with the expression of the Menkes defect.
1,316 citations
TL;DR: The predicted functional properties of the pWD gene together with its strong homology to Mc1, genetic mapping data and identification of four independent disease–specific mutations, provide convincing evidence that pWD is the Wilson disease gene.
Abstract: Wilson disease (WD) is an autosomal recessive disorder characterized by the toxic accumulation of copper in a number of organs, particularly the liver and brain. As shown in the accompanying paper, linkage disequilibrium & haplotype analysis confirmed the disease locus to a single marker interval at 13q14.3. Here we describe a partial cDNA clone (pWD) which maps to this region and shows a particular 76% amino acid homology to the Menkes disease gene, Mc1. The predicted functional properties of the pWD gene together with its strong homology to Mc1, genetic mapping data and identification of four independent disease-specific mutations, provide convincing evidence that pWD is the Wilson disease gene.
1,245 citations
TL;DR: This study offers the first description of a mitochondrial rRNA mutation leading to disease, the first cases of non–syndromic deafness caused by a mitochondrial DNA mutation and the first molecular genetic study of antibiotic–induced ototoxicity.
Abstract: Maternally transmitted non-syndromic deafness was described recently both in pedigrees with susceptibility to aminoglycoside ototoxicity and in a large Arab-Israeli pedigree. Because of the known action of aminoglycosides on bacterial ribosomes, we analysed the sequence of the mitochondrial rRNA genes of three unrelated patients with familial aminoglycoside-induced deafness. We also sequenced the complete mitochondrial genome of the Arab-Israeli pedigree. All four families shared a nucleotide 1555 A to G substitution in the 12S rRNA gene, a site implicated in aminoglycoside activity. Our study offers the first description of a mitochondrial rRNA mutation leading to disease, the first cases of non-syndromic deafness caused by a mitochondrial DNA mutation and the first molecular genetic study of antibiotic-induced ototoxicity.
1,085 citations
TL;DR: Sib pair and parent–child analysis revealed that the CAG repeat demonstrates only mild instability, and significant associations were also found between repeat length and age of death and onset of other clinical features.
Abstract: Huntington's disease (HD) is associated with the expansion of a CAG trinucleotide repeat in a novel gene. We have assessed 360 HD individuals from 259 unrelated families and found a highly significant correlation (r = 0.70, p = 10(-7)) between the age of onset and the repeat length, which accounts for approximately 50% of the variation in the age of onset. Significant associations were also found between repeat length and age of death and onset of other clinical features. Sib pair and parent-child analysis revealed that the CAG repeat demonstrates only mild instability. Affected HD siblings had significant correlations for trinucleotide expansion (r = 0.66, p < 0.001) which was not apparent for affected parent-child pairs.
1,059 citations
TL;DR: The initial observation of an expanded and unstable trinucleotide repeat in the Huntington's disease gene has now been confirmed and extended in 150 independent Huntington’s disease families and the analysis of the length and instability of individual repeats in members of these families has profound implications for presymptomatic diagnosis.
Abstract: The initial observation of an expanded and unstable trinucleotide repeat in the Huntington's disease gene has now been confirmed and extended in 150 independent Huntington's disease families. HD chromosomes contained 37-86 repeat units, whereas normal chromosomes displayed 11-34 repeats. The HD repeat length was inversely correlated with the age of onset of the disorder. The HD repeat was unstable in more than 80% of meiotic transmissions showing both increases and decreases in size with the largest increases occurring in paternal transmissions. The targeting of spermatogenesis as a particular source of repeat instability is reflected in the repeat distribution of HD sperm DNA. The analysis of the length and instability of individual repeats in members of these families has profound implications for presymptomatic diagnosis.
1,058 citations
TL;DR: Hemizygosity at the elastin locus is identified using genetic analyses in four familial and five sporadic cases of Williams syndrome, indicating that deletions involving oneElastin allele cause WS and implicate elast in hemizygosa in the pathogenesis of the disease.
Abstract: Williams syndrome (WS) is a developmental disorder affecting connective tissue and the central nervous system. A common feature of WS, supravalvular aortic stenosis, is also a distinct autosomal dominant disorder caused by mutations in the elastin gene. In this study, we identified hemizygosity at the elastin locus using genetic analyses in four familial and five sporadic cases of WS. Fluorescent in situ hybridization and quantitative Southern analyses confirmed these findings, demonstrating inherited and de novo deletions of the elastin gene. These data indicate that deletions involving one elastin allele cause WS and implicate elastin hemizygosity in the pathogenesis of the disease.
1,048 citations
TL;DR: These data demonstrate a gain of function associated with p53 mutations in addition to the loss of function shown previously to be associated with mutations in this tumour suppressor gene.
Abstract: We report that the expression of murine or human mutant p53 proteins in cells with no endogenous p53 proteins confers new or additional phenotypes upon these cells. Mutant p53 proteins expressed in cell lines lacking p53 resulted in either enhanced tumorigenic potential in nude mice ((10)3 cells) or enhanced plating efficiency in agar cell culture (human SAOS-2 cells). Also, mutant human p53 alleles, unlike the wild-type p53 protein, could also enhance the expression of a test gene regulated by the multi-drug resistance enhancer-promoter element. These data demonstrate a gain of function associated with p53 mutations in addition to the loss of function shown previously to be associated with mutations in this tumour suppressor gene.
TL;DR: Findings indicate that the t(2;13) generates a potentially tumorigenic fusion transcription factor consisting of intact PAX3 DNA binding domains, a truncated fork head DNA binding domain and C–terminal FKHR regions.
Abstract: We have examined the structure and expression of the products associated with the t(2;13)(q35;q14) translocation associated with alveolar rhabdomyosarcoma. The chromosome 13 gene (FKHR) is identified as a member of the fork head domain family of transcription factors characterized by a conserved DNA binding motif. Polymerase chain reaction analysis demonstrates that a 5'PAX3-3' FKHR chimaeric transcript is expressed in all eight alveolar rhabdomyosarcomas investigated. Immunoprecipitation experiments detect the predicted fusion protein. These findings indicate that the t(2;13) generates a potentially tumorigenic fusion transcription factor consisting of intact PAX3 DNA binding domains, a truncated fork head DNA binding domain and C-terminal FKHR regions.
TL;DR: It is demonstrated that arginine at position 192 specifies high activity PON whereas a glutamine specifies the low activity variant, and that PON maps to chromosome 7q21–22, proximal to the cystic fibrosis gene, in agreement with previous genetic linkage studies.
Abstract: The organophosphate cholinesterase inhibitor paraoxon is hydrolysed by serum paraoxonase/arylesterase. A genetic polymorphism of paraoxonase (PON) activity which determines high versus low paraoxon hydrolysis in human populations, may determine sensitivity to parathion poisoning. We demonstrate that arginine at position 192 specifies high activity PON whereas a glutamine specifies the low activity variant. Allele–specific probes or restriction enzyme analysis of amplified DNA allow for the genotyping of individuals. PON maps to chromosome 7q21–22, proximal to the cystic fibrosis gene, in agreement with previous genetic linkage studies.
TL;DR: Evidence is presented to support a model based on the possibility of recombination between homologous sequences located in intron 22 and upstream of the factor VIII gene that leads to an inversion of all intervening DNA and a disruption of the gene.
Abstract: Mutations in the factor VIII gene have been discovered for barely more than half of the examined cases of severe haemophilia A. To account for the unidentified mutations, we propose a model based on the possibility of recombination between homologous sequences located in intron 22 and upstream of the factor VIII gene. Such a recombination would lead to an inversion of all intervening DNA and a disruption of the gene. We present evidence to support this model and describe a Southern blot assay that detects the inversion. These findings should be valuable for genetic prediction of haemophilia A in approximately 45% of families with severe disease.
TL;DR: Immunohistochemistry shows a cytoplasmic localization of FMR–1, and the highest levels were observed in neurons, while glial cells contain very low levels, in epithelial tissues, and in adult testis, FMR-1 was detected only in spermatogonia.
Abstract: Fragile X mental retardation syndrome is caused by the unstable expansion of a CGG repeat in the FMR–1 gene. In patients with a full mutation, abnormal methylation results in suppression of FMR–1 transcription. FMR–1 is expressed in many tissues but its function is unknown. We have raised monoclonal antibodies specific for the FMR–1 protein. They detect 4–5 protein bands which appear identical in cells of normal males and of males carrying a premutation, but are absent in affected males with a full mutation. Immunohistochemistry shows a cytoplasmic localization of FMR–1. The highest levels were observed in neurons, while glial cells contain very low levels. In epithelial tissues, levels of FMR–1 were higher in dividing layers. In adult testis, FMR–1 was detected only in spermatogonia. FMR–1 was not detected in dermis and cardiac muscle except under pathological conditions.
TL;DR: A model system of direct gene transfer using a replication–defective adenoviral vector containing a β–galactosidase gene to transduce brain neurons is developed, suggesting an attractive and efficient alternative for neuronal gene transfer in vivo.
Abstract: Previous methods of in vivo gene transfer to differentiated neurons of the adult mammalian brain have been inefficient and associated with technical problems. We have therefore developed a model system of direct gene transfer using a replication-defective adenoviral vector containing a beta-galactosidase gene to transduce brain neurons. Following injection of purified high titre recombinant adenovirus into the caudate putamen of seven week old mice, lacZ activity was evident in neural components of the central nervous system (CNS) for at least 8 weeks post infection. The efficiency of adenoviral gene transfer was very high compared to other techniques, suggesting an attractive and efficient alternative for neuronal gene transfer in vivo.
TL;DR: The molecular characterization of extra–toes (Xt), which is a mouse model of GCPS, shows that a deficiency of Gli3 expression in the XtJ mutant is due to a deletion within the 3′ end of the gene.
Abstract: Greig cephalopolysyndactyly syndrome (GCPS) is an autosomal dominant disorder affecting limb and craniofacial development. Recently, the human GLI3 gene has been proposed to be a candidate gene for GCPS. Here we describe the molecular characterization of extra-toes (Xt), which is a mouse model of GCPS. The Xt heterozygotes show craniofacial defects and a polydactyly phenotype similar to GCPS. We show that a deficiency of Gli3 expression in the XtJ mutant is due to a deletion within the 3' end of the gene. Furthermore, structures affected in the mouse mutant and human syndrome were found to correlate with expression domains of Gli3 in mouse. These results strongly suggest that the deficiency of GLI3 function leads to GCPS.
TL;DR: The molecular analysis of a specific CAG repeat sequence in the Huntington's disease gene reveals a range of 30–70 repeats in affected individuals and 9–34 in normals, which suggests that normal gene function varies because of the size of the repeat in the normal range and a sex–specific modifying effect.
Abstract: The molecular analysis of a specific CAG repeat sequence in the Huntington's disease gene in 440 Huntington's disease patients and 360 normal controls reveals a range of 30-70 repeats in affected individuals and 9-34 in normals. We find significant negative correlations between the number of repeats on the HD chromosome and age at onset, regardless of sex of the transmitting parent, and between the number of repeats on the normal paternal allele and age at onset in individuals with maternally transmitted disease. This effect of the normal paternal allele may account for the weaker age at onset correlation between affected sib pairs with disease of maternal as opposed to paternal origin and suggests that normal gene function varies because of the size of the repeat in the normal range and a sex-specific modifying effect.
TL;DR: The construction of a phage contig and the isolation of candidate partial cDNAs for the Menkes disease gene are reported, leading to more accurate prenatal diagnosis of this severe disease and a better understanding of the cellular homeostasis of essential heavy metals.
Abstract: Menkes disease is a lethal-X linked recessive disorder associated with copper metabolism disturbance. We have recently mapped two chromosome breakpoints related to this disease in a 1 megabase yeast artificial chromosome contig at Xq13.3. We now report the construction of a phage contig and the isolation of candidate partial cDNAs for the Menkes disease gene. The candidate gene expresses an 8 kb message in all investigated tissues, and deletions were detected in 16% of 100 unrelated Menkes patients. The deduced partial protein sequence shared the GMTCXXC motif with bacterial metal resistance operons, suggesting a potential heavy metal binding protein. These findings should lead to more accurate prenatal diagnosis of this severe disease and a better understanding of the cellular homeostasis of essential heavy metals.
TL;DR: Genetic, biochemical and anatomical studies of dystrophin suggest that a number of distinct functions are subserved by its great structural diversity and may lead to an understanding of the cause and perhaps a rational treatment for muscular dystrophy.
Abstract: Duchenne and Becker muscular dystrophies are caused by defects of the dystrophin gene. Expression of this large X-linked gene is under elaborate transcriptional and splicing control. At least five independent promoters specify the transcription of their respective alternative first exons in a cell-specific and developmentally controlled manner. Three promoters express full-length dystrophin, while two promoters near the C terminus express the last domains in a mutually exclusive manner. Six exons of the C terminus are alternatively spliced, giving rise to several alternative forms. Genetic, biochemical and anatomical studies of dystrophin suggest that a number of distinct functions are subserved by its great structural diversity. Extensive studies of dystrophin may lead to an understanding of the cause and perhaps a rational treatment for muscular dystrophy.
TL;DR: Partial sequence of the cDNA shows a unique open reading frame containing putative metal binding motifs which have been found in heavy metal resistance genes in bacteria, which is a strong candidate for the Menkes disease gene.
Abstract: Menkes disease is an X-linked recessive disorder of copper metabolism resulting in death in early infancy. The gene has been mapped to band Xq13 based, in part, on a translocation breakpoint in a female with the disease, which was found to lie within 300 kilobases (kb) of the PGK-1 locus, allowing the isolation of a YAC clone spanning the breakpoint. Phage subclones from the breakpoint region were isolated and used to screen cDNA libraries. cDNA clones were found which detect an 8 kb transcript from normal individuals but show diminished or absent hybridization in Menkes disease patients. Partial sequence of the cDNA shows a unique open reading frame containing putative metal binding motifs which have been found in heavy metal resistance genes in bacteria. This gene is a strong candidate for the Menkes disease gene.
TL;DR: The results suggest that mutations in FMR–1 are directly responsible for fragile X syndrome, irrespective of possible secondary effects caused by FRAXA.
Abstract: The vast majority of patients with fragile X syndrome show a folate-sensitive fragile site at Xq27.3 (FRAXA) at the cytogenetic level, and both amplification of the (CGG)n repeat and hypermethylation of the CpG island in the 5' fragile X gene (FMR-1) at the molecular level. We have studied the FMR-1 gene of a patient with the fragile X phenotype but without cytogenetic expression of FRAXA, a (CGG)n repeat of normal length and an unmethylated CpG island. We find a single point mutation in FMR-1 resulting in an lle367Asn substitution. This de novo mutation is absent in the patient's family and in 130 control X chromosomes, suggesting that the mutation causes the clinical abnormalities. Our results suggest that mutations in FMR-1 are directly responsible for fragile X syndrome, irrespective of possible secondary effects caused by FRAXA.
TL;DR: Four mutations in the human gene encoding the β–subunit of rod cGMP phosphodiesterase (PDE β) that cosegregate with autosomal recessive retinitis pigmentosa, a degenerative disease of photoreceptors are found.
Abstract: We have found four mutations in the human gene encoding the β–subunit of rod cGMP phosphodiesterase (PDE β) that cosegregate with autosomal recessive retinitis pigmentosa, a degenerative disease of photoreceptors. In one family two affected siblings both carry allelic nonsense mutations at codons 298 and 531. Affected individuals have abnormal rod and cone electroretinograms. PDE β is the second member of the phototransduction cascade besides rhodopsin that is absent or altered as a cause of retinitis pigmentosa, suggesting that other members of this pathway may be defective in other forms of this disease.
TL;DR: This work has shown that the basic defect in these mice involves lesions in the gene which encodes haematopoietic cell phosphatase (HCP), and these mice provide excellent models for investigating the roles of phosphatases in haem atopoiesis and the nature of the genetic and cellular events linking impaired haematography to severe immunodeficiency and expression of systemic autoimmunity.
Abstract: Mice with the recessive motheaten (me) or the allelic viable motheaten (mev) mutations express a severe autoimmune and immunodeficiency syndrome. We have shown that the basic defect in these mice involves lesions in the gene which encodes haematopoietic cell phosphatase (HCP). These mice thus provide excellent models for investigating the roles of phosphatases in haematopoiesis and the nature of the genetic and cellular events linking impaired haematopoiesis to severe immunodeficiency and expression of systemic autoimmunity.
TL;DR: Heterozygous mice treated with a liver carcinogen, dimethylnitrosamine, showed a decreased survival time in comparison to treated wild type mice, suggesting that the p53–deficient mice may be useful for some in vivo carcinogenesis assays.
Abstract: Using gene targeting techniques, mice that have been generated with two germ–line p53 null alleles (homozygotes) develop normally but are highly susceptible to early onset spontaneous tumours. Here, we show that mice with a single null p53 allele (heterozygotes) produced in the same way are also susceptible to spontaneous tumours, but with a delayed onset compared to homozygotes. The most frequent tumour type in homozygotes was malignant lymphoma; in heterozygotes, osteosarcomas and soft tissue sarcomas predominated. Heterozygous mice treated with a liver carcinogen, dimethylnitrosamine, showed a decreased survival time in comparison to treated wild type mice, suggesting that the p53–deficient mice may be useful for some in vivo carcinogenesis assays.
TL;DR: Genetic linkage analysis in two unrelated families and Multilocus analysis with the location scores method established the best estimate for the location of the affected gene within a 14 centimorgan interval bracketed by D19S221 and D19 S222 loci.
Abstract: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) has been recently reported as a cause of stroke. It is characterized, in the absence of hypertension, by recurrent subcortical ischaemic strokes, starting in early or midadulthood and leading in some patients to dementia. Magnetic resonance imaging and pathological examination show numerous small subcortical infarcts and a diffuse leukoencephalopathy underlaid by a non–arteriosclerotic, non–amyloid angiopathy. We performed genetic linkage analysis in two unrelated families and assigned the disease locus to chromosome 19q12. Multilocus analysis with the location scores method established the best estimate for the location of the affected gene within a 14 centimorgan interval bracketed by D19S221 and D19S222 loci.
TL;DR: It is shown that the translocation t(12;16)(q13:p11) in malignant myxoid liposarcoma can be a fusion of the CHOP dominant negative transcription factor gene with a novel gene, FUS, which can result in fusion of.
Abstract: The search for tumour–specific markers is one of the chief goals in cancer biology. We show that the translocation t(12;16)(q13:p11) in malignant myxoid liposarcoma can be a fusion of the CHOP dominant negative transcription factor gene with a novel gene, FUS, which can result in fusion of the FUS glycine–rich protein with the whole CHOP coding region. The data support the concept that protein fusion may commonly occur in solid tumours resulting in tumour–specific markers of potential clinical importance. The data also indicate the importance of transcription disruption in the pathogenesis of solid tumours.
TL;DR: Adenovirus vectors appear to be a promising means for in vivo transfer of therapeutic genes into the central nervous system.
Abstract: The ability of a replication-deficient adenovirus vector to transfer a foreign gene into neural cells of adult rats in vivo has been analysed. A large number of neural cells (including neurons, astrocytes and ependymal cells) expressed an E. coli lacZ transgene for at least 45 days after inoculation of various brain areas. Injecting up to 3 x 10(5) pfu in 10 microliters did not result in any detectable cytopathic effects--these were only observed for very high titres of infection (> 10(7) pfu 10 microliters-1). Adenovirus vectors therefore appear to be a promising means for in vivo transfer of therapeutic genes into the central nervous system.
TL;DR: The PAX3 gene alterations are associated with two completely unrelated human diseases, paediatric solid tumour alveolar rhabdomyosarcoma and Leigh's syndrome.
Abstract: We have determined that PAX3 (found previously to be mutated in Waardenburg syndrome) is the chromosome 2 locus rearranged by the t(2;13)(q35;q14) translocation of the paediatric solid tumour alveolar rhabdomyosarcoma. The rearrangement breakpoints occur within an intron downstream of the paired box and homeodomain-encoding regions. Upstream PAX3 sequences hybridize to a novel transcript in t(2;13)-containing lines. Cloning and characterization of this novel transcript indicate that the translocation juxtaposes the PAX3 DNA binding elements with chromosome 13 sequences, suggesting formation of a hybrid transcription factor. Therefore, PAX3 gene alterations are associated with two completely unrelated human diseases.
TL;DR: In a series of Caucasian women with pregnancy–induced hypertension, a significant association of preeclampsia with a molecular variant of angiotensinogen, T235, found previously to be associated with essential hypertension is observed, which support a new pathophysiological interpretation of preeClampsia and of its relation to some forms of essential hypertension.
Abstract: Pregnancy–induced hypertension (PIH) is a heterogeneous disorder which complicates 5–7% of all pregnancies and remains a leading cause of maternal, fetal and neonatal morbidity and mortality. Severe preeclampsia is the most distinctive and life–threatening form; a multi–system disorder more common in first pregnancies, it is characterized by high blood pressure and proteinuria. In a series of Caucasian women with pregnancy–induced hypertension, we have observed a significant association of preeclampsia with a molecular variant of angiotensinogen, T235, found previously to be associated with essential hypertension. This finding is corroborated in a sample ascertained in Japan. Together, these observations support a new pathophysiological interpretation of preeclampsia and of its relation to some forms of essential hypertension.