Possible involvement of inefficient cleavage of preprovasopressin by signal peptidase as a cause for familial central diabetes insipidus.

Abstract

A transition of G to A at nucleotide position 279 in exon 1 ofthe vasopressin gene has been identified in patients with familial central diabetes insipidus. The mutation predicts an amino acid substitution of Thr (ACG) for Ala (GCG) at the COOH terminus of the signal peptide in preprovasopressin (preproVP). Translation in vitro of wild-type and mutant mRNAs produced 19-kD preproVPs. When translated in the presence of canine pancreatic rough microsomes, wild-type preproVP was converted to a 21-kD protein, whereas the mutant mRNA produced proteins of 21 kD and 23 kD. NH2-terminal amino acid sequence analysis revealed that the 21-kD proteins from the wild-type and the mutant were proVPs generated by the proteolytic cleavage of the 19-residue signal peptide and the addition of carbohydrate. Accordingly, mutant preproVP was cleaved at the correct site after Thr-19, but the efficiency of cleavage by signal peptidase was < 25% that observed for the wild-type preproVP, resulting in the formation of a predominant glycosylated but uncleaved 23-kD product. These data suggest that inefficient processing of preproVP produced by the mutant allele is possibly involved in the pathogenesis of diabetes insipidus in the affected individuals. (J. Clin. Invest. 1993. 91:2565-2571

A mutation which disrupts the hydrophobic core of the signal peptide of bilirubin UDP‐glucuronosyltransferase, an endoplasmic reticulum membrane protein, causes Crigler‐Najjar type IIs

“…Three naturally occurring mammalian signal peptide mutations have been described to date. These mutations were found in the secretory proteins, vasopressin, factor X, and parathyroid hormone [13][14][15][16]. The signal peptide mutation described in preparathyroid hormone was similar to the 15-Arg/B-UGT mutation, a disruption of the hydrophobic core of the signal peptide.…”

“…Signal peptide mutations that cause human disease have thus far only been identified in the secretory proteins: preprovasopressin [13], preproparathyroid hormone [ 14,15], and coagulation factor X [16]. In vasopressin and factor X, mutations were found respectively in the -1 and -3 positions of the carboxyl terminus of the signal peptide.…”

GPR48 Increases Mineralocorticoid Receptor Gene Expression

“…However, neither genotype showed any difference in hypothalamic vasopressin expression or renal vasopressin receptor 2 and aquaporin 2 expression, which are all associated with diabetes insipidus (Figure 3, B-E). [29][30][31] Aldosterone Resistance Exhibited by Gpr48 m/m Mice Water and electrolyte homeostasis are tightly controlled in the kidney. As shown in Table 1 Table S1).…”

Analysis of an IL-10 polymorphism in idiopathic pulmonary fibrosis

“…11 Five signal sequence mutations of human-secreted proteins, namely transforming growth factor-b 1 , 12 preprovasopressin, 13 preprofactor X, 14 lysosomal acid lipase (LAL) 15 and preproparathyroid hormone (prepro-PTH) 16 have been associated with human disease. Human IL-10 has an 18 amino-acid signal sequence.…”