Novel Homozygous Inactivating Mutation in the PCSK1 Gene in an Infant with Congenital Malabsorptive Diarrhea

Aerts, Laetitia; Terry, Nathalie A; Sainath, Nina N.; Torres, Clarivet; Martı́n, Martı́n G.; Ramos‐Molina, Bruno; Creemers, John W.M.

doi:10.3390/genes12050710

Cited by 13 publications

(12 citation statements)

References 36 publications

(67 reference statements)

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“…While for obvious reasons brain αMSH has never been measured in patients with inactivating PCSK1 mutations, levels of a variety of different peptide precursors are elevated in patient blood ( 61-63 ). New cases of severe pediatric PCSK1 insufficiency are reported each year (reviewed in ( 58 , 59 ); see also ( 64 , 65 )).…”

Section: Prohormone Convertasementioning

confidence: 99%

Obesity, POMC, and POMC-processing Enzymes: Surprising Results From Animal Models

Lindberg

Fricker

2021

Endocrinology

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Peptides derived from proopiomelanocortin (POMC) are well established neuropeptides and peptide hormones that perform multiple functions, including regulation of body weight. In humans and some animals, these peptides include alpha- and beta-melanocyte stimulating hormone (MSH). In certain rodent species, no beta-MSH is produced from POMC due to a change in the cleavage site. Enzymes that convert POMC into MSH include prohormone convertases (PCs), carboxypeptidases (CPs), and peptidyl-alpha-amidating monooxygenase (PAM). Humans and mice with inactivating mutations in either PC1/3 or carboxypeptidase E (CPE) are obese, which was assumed to result from defective processing of POMC into MSH. However, recent studies have shown that selective loss of either PC1/3 or CPE in POMC-expressing cells does not cause obesity. These findings suggest that defects in POMC processing cannot alone account for the obesity observed in global PC1/3 or CPE mutants. We propose that obesity in animals lacking PC1/3 or CPE activity depends, at least in part, on deficient processing of peptides in non-POMC-expressing cells either in brain and/or the periphery. Genetic background may also contribute to the manifestation of obesity.

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Section: Prohormone Convertasementioning

confidence: 99%

Obesity, POMC, and POMC-processing Enzymes: Surprising Results From Animal Models

Lindberg

Fricker

2021

Endocrinology

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“…Additional clinical case investigations have since led to the discovery of 34 more cases of congenital recessive PC1/3 deficiency, corresponding to 29 distinct PCSK1 variants ( Table 1 ). Cases up until 2019 [ 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ] are reviewed in a paper by Pépin et al [ 7 ]. Additional cases have since been reported [ 8 , 9 , 10 , 11 , 12 , 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

“…Cases up until 2019 [ 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ] are reviewed in a paper by Pépin et al [ 7 ]. Additional cases have since been reported [ 8 , 9 , 10 , 11 , 12 , 13 , 14 ]. All patients carried either homozygous or compound heterozygous PCSK1 variants and suffered from severe early malabsorptive diarrhea (within the first three months of life), which was the main clinical feature driving subsequent genetic PCSK1 analysis.…”

Section: Introductionmentioning

confidence: 99%

Rare Heterozygous PCSK1 Variants in Human Obesity: The Contribution of the p.Y181H Variant and a Literature Review

Dijck

Beckers

Diels

et al. 2022

Genes

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Recently, it was reported that heterozygous PCSK1 variants, causing partial PC1/3 deficiency, result in a significant increased risk for obesity. This effect was almost exclusively generated by the rare p.Y181H (rs145592525, GRCh38.p13 NM_000439.5:c.541T>C) variant, which affects PC1/3 maturation but not enzymatic capacity. As most of the identified individuals with the heterozygous p.Y181H variant were of Belgian origin, we performed a follow-up study in a population of 481 children and adolescents with obesity, and 486 lean individuals. We identified three obese (0.62%) and four lean (0.82%) p.Y181H carriers (p = 0.506) through sanger sequencing and high resulting melting curve analysis, indicating no association with obesity. Haplotype analysis was performed in 13 p.Y181H carriers, 20 non-carriers (10 with obesity and 10 lean), and two p.Y181H families, and showed identical haplotypes for all heterozygous carriers (p < 0.001). Likewise, state-of-the-art literature concerning the role of rare heterozygous PCSK1 variants implies them to be rarely associated with monogenic obesity, as first-degree carrier relatives of patients with PC1/3 deficiency are mostly not reported to be obese. Furthermore, recent meta-analyses have only indicated a robust association for scarce disruptive heterozygous PCSK1 variants with obesity, while clinical significance is less or sometimes lacking for most nonsynonymous variants.

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“…To our knowledge, 32 PC1/3 deficient patients have been reported in the literature. Among them, 28 (87.5%) patients had homozygous mutations and only 4 (12.5%) were compound heterozygotes (6)(7)(8)(9)(10). Depending on the location of the mutation site and the type of mutation, the impact on the final result of protein synthesis and enzyme activity frequently differs.…”

Section: Introductionmentioning

confidence: 99%

Modulation of PC1/3 activity by a rare double-site homozygous mutation

Chen²,

Sun³

et al. 2022

Front. Pediatr.

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ObjectivesPreprotein convertase 1/3 deficiency is a rare autosomal recessive disorder in which patients present with malabsorptive diarrhea and a series of symptoms of endocrine disorders such as polydipsia, reactive hypoglycemia, growth hormone deficiency, hypothyroidism, adrenal insufficiency, and early onset obesity. In its essence, pituitary hormone deficiency is caused by insufficient cleavage of pituitary prohormones. Here, we describe a female child with a rare double-site homozygous mutation in PCSK1 (Proprotein convertase subtilisin/kexin-type 1) gene, and thereby intend to investigate the relationship between these novel mutation sites and changes in protein synthesis and function.MethodsWe tested this patient's blood and urine fecal indicators of infection, blood electrolytes, and relevant endocrine hormone levels in the laboratory. Next Generation Sequencing was applied to screen the patient's DNA. Western Blot was performed to evaluate the mutant protein's expression. The enzymatic activity was measured as the rate of cleavage of a synthetic fluorogenic substrate in a specific solution.ResultsWe found that this patient presented shortly after birth with uncorrectable diarrhea and symptoms of metabolic acidosis with hypothyroidism. Next Generation Sequencing revealed that a rare double-site homozygous missense mutation, c.763G > A (p.G255R) and c.758C > T (p.S253L), were detected in exon 7 of PCSK1 (Proprotein convertase subtilisin/kexin-type 1) gene on chromosome 5 of the patient. Western blotting revealed that there was no significant decrease in protein synthesis levels in the mutant phenotype compared to the wild type. Compared with WT type, the proteins expressed by the mutations showed a significant decrease in the enzyme activity towards the fluorescent substrates. However, neither the single site mutation p.S253L or p.G255R, nor the double-site mutation of both, all showed no significant differences from each other.ConclusionsThese two missense mutations have not been reported before, and it is even rarer to find homozygous variation of two sites in one patient. This study identifies two novel mutations for the first time and further investigates the changes in protein synthesis and enzyme activity, providing a new pathway to continue to explore the pathogenesis of diseases associated with the function of PC1/3.

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Novel Homozygous Inactivating Mutation in the PCSK1 Gene in an Infant with Congenital Malabsorptive Diarrhea

Cited by 13 publications

References 36 publications

Obesity, POMC, and POMC-processing Enzymes: Surprising Results From Animal Models

Obesity, POMC, and POMC-processing Enzymes: Surprising Results From Animal Models

Rare Heterozygous PCSK1 Variants in Human Obesity: The Contribution of the p.Y181H Variant and a Literature Review

Modulation of PC1/3 activity by a rare double-site homozygous mutation

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