Enteroendocrine Dysfunction in Two Saudi Sisters

Ahmed, Amna Basheer M.; Alsaleem, Badr

doi:10.1159/000511761

Cited by 4 publications

(7 citation statements)

References 24 publications

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“…The form and severity of hormonal insufficiency vary from patient to patient with PC1/3 deficiency. To date, there have been 32 cases of PCSK1 deficiency recorded so far, with patients presenting a varied range of symptoms (6,8,9). The first patient with a PCSK1 mutation was reported by O'Rahilly et al in 1995 (11); of total 33 patients diagnosed (including the one we reported) (see Table 2), all presented with malabsorptive diarrhea before the age of 3 years, 60.6% (20/33) in males and 39.4% (13/33) However, except for diarrhea, the three patients who all had the c.927C > G variant and the two patients who all had the c.1350_1353del (p. D451fs) mutation had little in common.…”

Section: Discussionmentioning

confidence: 99%

“…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%

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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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Section: Discussionmentioning

confidence: 99%

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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“…genes) [92]; celiac disease (CPED1 gene) [93]; hereditary spherocytosis type 3 (SPTA1 gene) [89]; developmental delay, cerebellar hypoplasia, and myoclonic seizures (KCNMA1 gene) [74]; Cenani-Lenz syndrome (APC gene) [74]; Sjogren-Larsson syndrome (ELOVL4 gene) [74]; autism spectrum disorder (multigene) [94]; congenital heart disease (PRKD1 gene) [95]; ciliopathies [96]; Parkinsonism (PLA2G6 gene) [97]; retinal dystrophies (CLRN1, ABCA4, CERKL, AGBL5, CDH16, and DNAJC17 genes) [98][99][100]; Pediatric Asthma [101]; cardiovascular genetic diseases (LDLR gene) [102]; enteroendocrine dysfunction (PCSK1) [103]; tricho-hepato-enteric syndrome (TTC37 and SKIV2L) [104]; Wolcott-Rallison syndrome (EIF2AK3) [105], Fanconi-Bickel syndrome (SLC2A2) [105] and Alström syndrome (Exon 19 Skipping in ALMS1 Gene) [106,107]; using whole exome or whole genome analysis revealed disease markers in Saudi population. Families with autosomal recessive retinal dystrophies from various ethnicity including Saudis were analysed for candidate genes using WES, 45 unique deleterious variants including 18 novel variants observed [108].…”

Section: Other Genetic Diseasesmentioning

confidence: 99%

Heterogeneity in biomarkers, mitogenome and genetic disorders of Arab population with special emphasis on large-scale whole-exome sequencing

Borgio

2021

Arch Med Sci

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More than 25 million DNA variations were discovered as novel including major alleles from Arab population. Exome studies on Arabs discovered >3000 novel nucleotide variants associated with >1200 rare genetic disorders. Reclassification of many pathogenic variant into benign through the Arab database enhance building a detailed and comprehensive map of Arab morbid genome. Intellectual disability stands first with the combined and observed carrier frequency. Genome studies and advanced computational biology discovered interesting novel candidate disease marker variations in many genes from consanguineous families with intellectual disability, neurogenetic disorders, blood and bleeding disorder and rare genetic diseases. Pathogenic variants in C12orf57 gene are prominently associated with the etiology of developmental delay/intellectual impairment. Arab mitogenome exposed hundreds of variations in mtDNA genome and its association with obesity. Further study is needed in genomics to fully comprehend the molecular abnormalities and associated pathogenesis that cause inherited disorders in Arab ancestries.

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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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Enteroendocrine Dysfunction in Two Saudi Sisters

Cited by 4 publications

References 24 publications

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

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

Heterogeneity in biomarkers, mitogenome and genetic disorders of Arab population with special emphasis on large-scale whole-exome sequencing

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

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