Proprotein Convertase 1/3 Deficiency

A number sign (#) is used with this entry because of evidence that proprotein convertase 1/3 deficiency is caused by homozygous or compound heterozygous mutation in the PC1 gene (PCSK1; 162150) on chromosome 5q15.

Clinical Features

O'Rahilly et al. (1995) reported a 43-year-old woman who was referred for the evaluation of symptoms suggestive of postprandial hypoglycemia. She had a history of severe childhood obesity, with weight of 36 kg at the age of 3 years, for which she had been treated successfully with diet. Development of secondary sexual characteristics was normal, but she had primary amenorrhea. At the age of 30, ovulation was induced with gonadotropins, and she became pregnant and delivered healthy quadruplets. The pregnancy was complicated by gestational diabetes mellitus that required treatment with insulin. After the pregnancy, her fasting plasma glucose level was normal, but persistent amenorrhea prevailed. Plasma concentrations of proinsulin, and plasma insulin concentrations were low, suggesting an abnormality of proinsulin processing. In addition, there was evidence of impaired processing of proopiomelanocortin (POMC; 176830), secondary hypocortisolism, and hypogonadotropic hypogonadism, suggesting the possibility of a more generalized defect related to impaired processing of prohormones. Since proinsulin has about 5% of the biologic activity of insulin, this patient's beta cells had compensated for the failure of normal processing in the basal state. The authors speculated that a combination of impaired glucose tolerance and reactive hypoglycemia 5 hours after a meal was probably related to the considerably slower clearance of proinsulin. The findings in the patient suggested a defect in prohormone convertase 1, which cleaves proinsulin between the 32 position and the 33 position, rather than in proconvertase-2 (162151), which cleaves it between the 65 position and the 66 position. O'Rahilly et al. (1995) noted that the only living relatives the patient had were her 4 children; all had a slight increase in their fasting plasma proinsulin concentration relative to the concentration of 32,33 split proinsulin, consistent with a mild defect in PC1 activity. The authors noted that in the mouse, an obesity-diabetes syndrome elicited by a genetic defect in a prohormone processing pathway was described by Naggert et al. (1995); see 114855.

Jackson et al. (1997) noted that 2 specific syndromes caused by abnormalities in the secretory products of pancreatic beta cells had been defined; mutations in the insulin gene that lead to the production of biologically ineffective insulin (see 176730.0005), and mutations in the insulin gene that affect the cleavage of proinsulin which lead to the secretion of excessive amounts of proinsulin (see 176730.0003).

Jackson et al. (2003) reported a female infant who presented on the third postnatal day with persistent, treatment-refractory diarrhea. Malabsorption of monosaccharides and fat was confirmed. She was hypocortisolemic, became grossly obese despite low calorie intake, and suffered a fatal cardiopulmonary arrest at age 18 months. Small intestinal biopsies showed persistent, patchy, normoplastic villous atrophy with occasional inflammatory cells in the lamina propria. Plasma proinsulin was high and insulin low, suggesting a processing defect. Reexamination of the patient originally reported by O'Rahilly et al. (1995) revealed a lifelong history of gastrointestinal disturbance and small intestinal malabsorption. Further studies showed an increase in progastrin and proglucagon, showing that prohormone processing in enteroendocrine cells was abnormal.

Farooqi et al. (2007) described a 6-year-old boy, born of consanguineous Libyan parents, who had watery diarrhea with malabsorption of monosaccharides and fat that began shortly after birth. At 4 years of age, he developed polyuria and polydipsia suggestive of diabetes insipidus, although serum osmolality was not elevated, and a water deprivation test was nondiagnostic. At 6 years of age, the boy was evaluated for severe obesity and was found to have an appropriate leptin (164160) level but a highly abnormal insulin to proinsulin ratio. Evaluation of his metabolic phenotype revealed a degree of hyperphagia comparable to that seen in patients with melanocortin-4 receptor mutations (155541) and a normal basal metabolic rate. He had a low serum cortisol level and ACTH precursor levels were found to be markedly elevated, consistent with a degree of impaired proopiomelanocortin (POMC; 176830) processing, whereas plasma ACTH levels were normal. He also had an elevated TSH with a free T(4) concentration at the lower end of the normal range, consistent with hypothalamic hypothyroidism.

Molecular Genetics

Jackson et al. (1997) studied the 43-year-old woman reported by O'Rahilly et al. (1995) and confirmed the suspicion of an abnormality of prohormone convertase-1 by identifying compound heterozygous mutations in the PC1 gene (162150.0001-162150.0002).

In an infant with obesity, elevated prohormones, and refractory diarrhea, Jackson et al. (2003) identified compound heterozygosity for mutations in the PC1 gene (162150.0003-162150.0004).

In a 6-year-old boy, born of consanguineous parents of Libyan origin, with persistent diarrhea and severe hyperphagia and obesity, Farooqi et al. (2007) identified homozygosity for a mutation in the PCSK1 gene (S307L; 162150.0006). Both parents were heterozygous for the mutation and were not obese; the mutation was not found in 100 control alleles of Arab origin. Farooqi et al. (2007) concluded that the gastrointestinal phenotype is a major feature of PC1/3 deficiency and that the obesity is largely driven by an increase in food intake.