Alternative titles; symbols
ORPHA: 71528; DO: 0111698; MONDO: 0010961;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 5q15 | Endocrinopathy due to proprotein convertase 1/3 deficiency | 600955 | Autosomal recessive | 3 | PCSK1 | 162150 |
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.
Proprotein convertase-1/3 deficiency is an autosomal recessive disorder characterized by neonatal severe generalized malabsorptive diarrhea and failure to thrive. As the disease progresses, additional endocrine abnormalities develop, including diabetes insipidus, growth hormone deficiency, primary hypogonadism, adrenal insufficiency, and hypothyroidism (summary by Wilschanski et al., 2014).
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.
Wilschanski et al. (2014) reported 4 sibs, born to consanguineous Arab families, with proprotein convertase 1/3 deficiency. The oldest sib (patient II-2) presented with severe malabsorptive diarrhea with steatorrhea and required parenteral nutrition until 5 years of age. Intestinal biopsy showed nonspecific enteropathy with mild villous atrophy. She was eventually diagnosed with central hypothyroidism and growth hormone deficiency, and she had self-limited episodes of diabetes insipidus. She became obese by 6 years of age. Two younger sibs (patients II-3 and II-4) died at 9 days and 5 months of age due to intractable seizures which were thought to be due to an unrelated disorder. Patient II-4 also had diarrhea and hypoparathyroidism. The youngest sib (patient II-5) was a 1-year-old boy who had neonatal diarrhea and required parenteral in the first year of life.
Pepin et al. (2019) reported a patient, born to consanguineous Turkish parents, who presented in the first week of life with watery diarrhea, transient hypoglycemia, and micropenis. A duodenal biopsy showed nonspecific partial villous atrophy. He had episodic central diabetes insipidus starting in the neonatal period. He was diagnosed with growth hormone deficiency and hypogonadotrophic hypogonadism at 2 months of age, and central hypothyroidism was diagnosed at 12 months of age. He required parenteral nutrition for 3 years, but at 2 years of age he developed compulsive food intake and became obese.
Martin et al. (2013) reported 13 patients from 11 families with severe malabsorptive diarrhea and mutation in the PCSK1 gene. All of the patients were born at full term and presented with dehydration, metabolic acidosis, and diarrhea in the first 2 months of life. Intestinal biopsies were normal in 11 patients and showed mild villous atrophy in 2 patients. Twelve patients required intravenous nutrition, and the patient who was not treated with intravenous nutrition had the most severe failure to thrive. Dependency on parenteral nutrition diminished with time, but diarrhea continued. Eight patients had postprandial hypoglycemia and 7 patients had increased serum proinsulin levels. Eleven patients had polydipsia and polyuria, and 8 patients were diagnosed with diabetes insipidus at an average age of 18 months. Central adrenal insufficiency was diagnosed in 8 patients between 1 month and 5.5 years of age. Central hypothyroidism was diagnosed in 8 cases between 1 and 17 months of age. Four patients were diagnosed with growth hormone deficiency.
Yourshaw et al. (2013) reported a patient who presented at 3 weeks of age with persistent diarrhea and metabolic acidosis. He was diagnosed with diabetes insipidus after 4 years of age. Laboratory testing demonstrated elevated proinsulin, slightly elevated thyroid-stimulating hormone, and low serum insulin-like growth factor and insulinlike growth hormone-binding protein-3. Small and large bowel mucosa was histologically normal except for the loss of PC1/3 positive neuroendocrine cells.
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.
Wilschanski et al. (2014) identified a homozygous missense mutation in the PCSK1 gene (N309K; 162150.0007) in 4 Arab sibs, born to consanguineous parents, with proprotein convertase-1 deficiency. The mutation was not present in the Exome Variant Server database. When PCSK1 with the N209K mutation was expressed in HEK293 and Neuro2A cells, the secreted enzyme showed no catalytic activity and was not processed to the 66-kD form, indicating that there was no self-cleavage. Radiolabeling experiments in Neuro2A cells showed that PCSK1 with the N209K mutation was able to undergo prodomain removal and generate an 87-kD form.
In a patient, born to consanguineous Turkish parents, with proprotein convertase-1 deficiency, Pepin et al. (2019) identified a homozygous nonsense mutation in the PCSK1 gene (R199X; 162150.0008). The mutation, which was found by whole-exome sequencing, was present in heterozygous state in the parents.
Martin et al. (2013) reported homozygous mutations in the PCSK1 gene in 13 patients with proprotein convertase-1 deficiency from 11 families, 10 of which were consanguineous. One patient (patient 2) had 2 homozygous mutations (G209R and P258T). The mutations included 5 missense, 4 nonsense, 1 deletion (162150.0011), and 2 splice site mutations (IVS10+1G-T, 162150.0009; IVS10+1G-A, 162150.0010). Expression of PCKS1 with each mutation in HEK293 cells resulted in most in lack of secreted enzyme activity, including all of the nonsense mutations and the deletion. PCKS1 with the F548S mutation was secreted but was inactive, and PCKS1 with the P258T or N432K mutations had reduced enzyme activity. None of the mutations were present in the dbSNP and 1000 Genomes Project databases.
Farooqi, I. S., Volders, K., Stanhope, R., Heuschkel, R., White, A., Lank, E., Keogh, J., O'Rahilly, S., Creemers, J. W. M. Hyperphagia and early-onset obesity due to a novel homozygous missense mutation in prohormone convertase 1/3. J. Clin. Endocr. Metab. 92: 3369-3373, 2007. [PubMed: 17595246] [Full Text: https://doi.org/10.1210/jc.2007-0687]
Jackson, R. S., Creemers, J. W. M., Farooqi, I. S., Raffin-Sanson, M.-L., Varro, A., Dockray, G. J., Holst, J. J., Brubaker, P. L., Corvol, P., Polonsky, K. S., Ostrega, D., Becker, K. L., and 10 others. Small-intestinal dysfunction accompanies the complex endocrinopathy of human proprotein convertase 1 deficiency. J. Clin. Invest. 112: 1550-1560, 2003. [PubMed: 14617756] [Full Text: https://doi.org/10.1172/JCI18784]
Jackson, R. S., Creemers, J. W. M., Ohagi, S., Raffin-Sanson, M.-L., Sanders, L., Montague, C. T., Hutton, J. C., O'Rahilly, S. Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nature Genet. 16: 303-306, 1997. [PubMed: 9207799] [Full Text: https://doi.org/10.1038/ng0797-303]
Martin, M. G., Lindberg, I., Solorzano-Vargas, R. S., Wang, J., Avitzur, Y., Bandsma, R., Sokollik, C., Lawrence, S., Pickett, L. A., Chen, Z., Egritas, O., Dalgic, B., and 12 others. Congenital proprotein convertase 1/3 deficiency causes malabsorptive diarrhea and other endocrinopathies in a pediatric cohort. Gastroenterology 145: 138-148, 2013. [PubMed: 23562752] [Full Text: https://doi.org/10.1053/j.gastro.2013.03.048]
Naggert, J. K., Fricker, L. D., Varlamov, O., Nishina, P. M., Rouille, Y., Steiner, D. F., Carroll, R. J., Paigen, B. J., Leiter, E. H. Hyperproinsulinaemia in obese fat/fat mice associated with a carboxypeptidase E mutation which reduces enzyme activity. Nature Genet. 10: 135-142, 1995. [PubMed: 7663508] [Full Text: https://doi.org/10.1038/ng0695-135]
O'Rahilly, S., Gray, H., Humphreys, P. J., Krook, A., Polonsky, K. S., White, A., Gibson, S., Taylor, K., Carr, C. Brief report: impaired processing of prohormones associated with abnormalities of glucose homeostasis and adrenal function. New Eng. J. Med. 333: 1386-1390, 1995. [PubMed: 7477119] [Full Text: https://doi.org/10.1056/NEJM199511233332104]
Pepin, L., Colin, E., Tessarech, M., Rouleau, S., Bouhours-Nouet, N., Bonneau, D., Coutant, R. A new case of PCSK1 pathogenic variant with congenital proprotein convertase 1/3 deficiency and literature review. J. Clin. Endocr. Metab. 104: 985-993, 2019. [PubMed: 30383237] [Full Text: https://doi.org/10.1210/jc.2018-01854]
Wilschanski, M., Abbasi, M., Blanco, E., Lindberg, I., Yourshaw, M., Zangen, D., Berger, I., Shteyer, E., Pappo, O., Bar-Oz, B., Martin, M. G., Elpeleg, O. A novel familial mutation in the PCSK1 gene that alters the oxyanion hole residue of proprotein convertase 1/3 and impairs its enzymatic activity. PLoS One 9: e108878, 2014. [PubMed: 25272002] [Full Text: https://doi.org/10.1371/journal.pone.0108878]
Yourshaw, M., Solorzano-Vargas, R. S., Pickett, L. A., Lindberg, I., Wang, J., Cortina, G., Pawlikowska-Haddal, A., Baron, H., Venick, R. S., Nelson, S. F., Martin, M. G. Exome sequencing finds a novel PCSK1 mutation in a child with generalized malabsorptive diarrhea and diabetes insipidus. J. Pediat. Gastroent. Nutr. 57: 759-767, 2013. [PubMed: 24280991] [Full Text: https://doi.org/10.1097/MPG.0b013e3182a8ae6c]