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. 2013 Jul;145(1):138-148.
doi: 10.1053/j.gastro.2013.03.048. Epub 2013 Apr 2.

Congenital Proprotein Convertase 1/3 Deficiency Causes Malabsorptive Diarrhea and Other Endocrinopathies in a Pediatric Cohort

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Free PMC article

Congenital Proprotein Convertase 1/3 Deficiency Causes Malabsorptive Diarrhea and Other Endocrinopathies in a Pediatric Cohort

Martín G Martín et al. Gastroenterology. .
Free PMC article

Abstract

Background & aims: Proprotein convertase 1/3 (PC1/3) deficiency, an autosomal-recessive disorder caused by rare mutations in the proprotein convertase subtilisin/kexin type 1 (PCSK1) gene, has been associated with obesity, severe malabsorptive diarrhea, and certain endocrine abnormalities. Common variants in PCSK1 also have been associated with obesity in heterozygotes in several population-based studies. PC1/3 is an endoprotease that processes many prohormones expressed in endocrine and neuronal cells. We investigated clinical and molecular features of PC1/3 deficiency.

Methods: We studied the clinical features of 13 children with PC1/3 deficiency and performed sequence analysis of PCSK1. We measured enzymatic activity of recombinant PC1/3 proteins.

Results: We identified a pattern of endocrinopathies that develop in an age-dependent manner. Eight of the mutations had severe biochemical consequences in vitro. Neonates had severe malabsorptive diarrhea and failure to thrive, required prolonged parenteral nutrition support, and had high mortality. Additional endocrine abnormalities developed as the disease progressed, including diabetes insipidus, growth hormone deficiency, primary hypogonadism, adrenal insufficiency, and hypothyroidism. We identified growth hormone deficiency, central diabetes insipidus, and male hypogonadism as new features of PCSK1 insufficiency. Interestingly, despite early growth abnormalities, moderate obesity, associated with severe polyphagia, generally appears.

Conclusions: In a study of 13 children with PC1/3 deficiency caused by disruption of PCSK1, failure of enteroendocrine cells to produce functional hormones resulted in generalized malabsorption. These findings indicate that PC1/3 is involved in the processing of one or more enteric hormones that are required for nutrient absorption.

Conflict of interest statement

Disclosures: None of the authors have potential financial, professional, or personal conflicts to disclose.

Figures

Figure 1
Figure 1. Pedigrees and mutations in PCSK1
Pedigrees of families studied, showing genotypes (./. NA, 0/0 WT, 0/1 heterozygous, 1/1 homozygous) and Sanger sequencing results for proband, and unaffected control. The proband(s) that were sequenced are indicated by the black square (male) or circle (female). Homozygote mutations within each family are indicated by MM; heterozygotes by MN; normal on both alleles by NN; and not assessed as NA. A slash through the symbol indicates that the subject is deceased, and a double line between the parents indicates a consanguineous union.
Figure 2
Figure 2. Domain structure and mutation locations within prepro-PC1/3
Overview of PC1/3 protein regions with locations of mutations presented in this study and previously published mutations.
Figure 3
Figure 3. Location of 5 missense mutations in the PC1/3 gene family in conserved domains
Alignment of missense variants to members of PC1/3 gene family.
Figure 4
Figure 4. Western blot of PC1/3 wild-type and mutant protein expression
HEK293 cells were transfected with empty vector (E), wild-type PC1/3 (WT), or PC1/3s containing novel mutations. Media and cells were subjected to Western blotting using amino-terminally directed PC1/3 primary antiserum. Truncation mutations are shown in Panel A, and missense mutations are shown in Panel B. β-actin was used as a loading control.
Figure 4
Figure 4. Western blot of PC1/3 wild-type and mutant protein expression
HEK293 cells were transfected with empty vector (E), wild-type PC1/3 (WT), or PC1/3s containing novel mutations. Media and cells were subjected to Western blotting using amino-terminally directed PC1/3 primary antiserum. Truncation mutations are shown in Panel A, and missense mutations are shown in Panel B. β-actin was used as a loading control.
Figure 5
Figure 5. Enzymatic activity of wild-type PC1/3 and novel PC1/3 variants
The enzymatic activities of secreted PC1/3 proteins in conditioned medium were assayed using a fluorogenic assay. Four replicates per transfection condition were assayed in triplicate, and maximum rates were normalized to WT PC1/3. Maximum activity rates are shown as the mean ±S.D., n=4 wells. Data represent one of 3 independent experiments. Bars represent mean ± standard deviation, and unpaired Student’s t-test was used to assess difference between mutant and WT activities with *:P-value <0.001, **:P-value <0.05. All experiments were independently repeated in triplicate wells at least three times, with similar results.

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