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Abstract

Investigation of one kindred with autosomal recessive isolated hypoparathyroidism, which had resulted from a consanguineous marriage, has identified a g to c substitution in the first nucleotide of intron 2 of the parathyroid hormone (PTH) gene. This donor splice mutation could be detected by restriction enzyme cleavage with Ddel, and this revealed that the patients were homozygous for the mutant alleles, the unaffected relatives were heterozygous, and unrelated normals were homozygous for the wild type alleles. Defects in messenger RNA splicing were investigated by the detection of illegitimate transcription of the PTH gene in lymphoblastoid cells. The mutation resulted in exon skipping with a loss of exon 2, which encodes the initiation codon and the signal peptide, thereby causing parathyroid hormone deficiency.

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Ovalbumin gene: evidence for a leader sequence in mRNA and DNA sequences at the exon-intron boundaries.

F Gannon, R Breathnach, C Benoist … (1978)

Selected regions of cloned EcoRI fragments of the chicken ovalbumin gene have been sequenced. The positions where the sequences coding for ovalbumin mRNA (ov-mRNA) are interrupted in the genome have been determined, and a previously unreported interruption in the DNA sequences coding for the 5' nontranslated region of the messenger has been discovered. Because directly repeated sequences are found at exon-intron boundaries, the nucleotide sequence alone cannot define unique excision-ligation points for the processing of a possible ov-mRNA precursor. However, the sequences in these boundary regions share common features; this leads to the proposal that there are, in fact, unique excision-ligation points common to all boundaries.

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Illegitimate transcription: transcription of any gene in any cell type.

Suzana A Kahn, Bonnie Kaplan, J P Concordet … (1989)

Using in vitro amplification of cDNA by the polymerase chain reaction, we have detected spliced transcripts of various tissue-specific genes (genes for anti-Müllerian hormone, beta-globin, aldolase A, and factor VIIIc) in human nonspecific cells, such as fibroblasts, hepatoma cells, and lymphoblasts. In rats, erythroid- and liver-type pyruvate kinase transcripts were also detected in brain, lung, and muscle. The abundance of these "illegitimate" transcripts is very low; yet, their existence and the possibility of amplifying them by the cDNA polymerase chain reaction provide a powerful tool to analyze pathological transcripts of any tissue-specific gene by using any accessible cell.

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Mutation of the signal peptide-encoding region of the preproparathyroid hormone gene in familial isolated hypoparathyroidism.

A. Arnold, T Gardella, Jessica S. Horst … (1990)

Preproparathyroid hormone (preproPTH) gene mutation has been proposed as a cause of familial isolated hypoparathyroidism (FIH). We cloned the preproPTH alleles of a patient with autosomal dominant FIH and sequenced the coding regions, 5' flanking regions, and splice junctions. The putatively abnormal (based on previous linkage studies) allele differed from the other allele's normal sequence at only one nucleotide. This T to C point mutation changes the codon for position 18 of the 31 amino acid prepro sequence from cysteine to arginine, disrupting the hydrophobic core of the signal sequence. Because the hydrophobic core is required by secreted proteins for efficient translocation across the endoplasmic reticulum, the mutant protein is likely to be inefficiently processed. Indeed, in vitro studies demonstrated dramatically impaired processing of the mutant preproPTH to proPTH. In summary, we observed a point mutation in the signal peptide-encoding region of a preproPTH gene in one FIH kindred and demonstrated a functional defect caused by the mutation. Mutation of the signal sequence constitutes a novel pathophysiologic mechanism in man, and further study may yield important insights both into this form of hormone deficiency and into the role of signal sequences in human physiology.

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PubMed ID:: 1302009

DOI:: 10.1038/ng0592-149

ScienceOpen disciplines: Chemistry

Keywords: Base Sequence,DNA,genetics,DNA Mutational Analysis,Female,Genes, Recessive,Humans,Hypoparathyroidism,Male,Molecular Sequence Data,Parathyroid Hormone,Pedigree,RNA Splicing

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ScienceOpen disciplines: Chemistry

Keywords: Base Sequence, DNA, genetics, DNA Mutational Analysis, Female, Genes, Recessive, Humans, Hypoparathyroidism, Male, Molecular Sequence Data, Parathyroid Hormone, Pedigree, RNA Splicing

A donor splice site mutation in the parathyroid hormone gene is associated with autosomal recessive hypoparathyroidism.

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Synthesis of 2-trifluoromethylated piperidines and azepanes

Most cited references 19

Ovalbumin gene: evidence for a leader sequence in mRNA and DNA sequences at the exon-intron boundaries.

Illegitimate transcription: transcription of any gene in any cell type.

Mutation of the signal peptide-encoding region of the preproparathyroid hormone gene in familial isolated hypoparathyroidism.

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