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Related Experiment Video

Updated: Jun 13, 2025

A High-Throughput Luciferase Assay to Evaluate Proteolysis of the Single-Turnover Protease PCSK9
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Pathogenic Deep Intronic PCSK1 Variant Causes Proprotein Convertase 1/3 Deficiency in a Family.

Leah M Huber1, Aslı Subaşıoğlu2,3, Dorota Garczarczyk-Asim1

  • 1Department of Pediatrics I, Medical University of Innsbruck, Innsbruck, Austria.

Clinical Genetics
|February 1, 2025
PubMed
Summary
This summary is machine-generated.

Proprotein convertase 1/3 (PC1/3) deficiency, crucial for energy homeostasis, can be caused by deep intronic PCSK1 variants leading to aberrant splicing. Extended genetic testing is vital for timely diagnosis of this polyendocrinopathy.

Keywords:
PCSK1congenital malabsorptive diarrheaendocrinopathyobesityproprotein convertase 1/3

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Area of Science:

  • Genetics
  • Molecular Biology
  • Endocrinology

Background:

  • Proprotein convertase 1/3 (PC1/3), encoded by PCSK1, is vital for activating protein precursors involved in energy homeostasis.
  • Biallelic loss-of-function mutations in PCSK1 cause polyendocrinopathy, with 34 patients previously reported.
  • PC1/3 deficiency diagnosis can be challenging, especially when standard exome sequencing reveals no mutations.

Purpose of the Study:

  • To investigate the genetic basis of PC1/3 deficiency in an infant with congenital malabsorptive diarrhea and subsequent obesity.
  • To identify the underlying genetic cause when initial exome sequencing is negative.
  • To elucidate the mechanism of a novel deep intronic variant in PCSK1.

Main Methods:

  • Exome sequencing (ES) was performed on an infant presenting with malabsorptive diarrhea and obesity.
  • Transcript analysis was conducted to identify aberrant PCSK1 transcripts.
  • A deep intronic variant (c.1196+2681T>A) was identified and segregated within the family.
  • Minigene assays were used to confirm the functional impact of the intronic variant.

Main Results:

  • Exome sequencing did not reveal mutations in coding regions, despite clinical suspicion of PC1/3 deficiency.
  • Transcript analysis identified an aberrant PCSK1 transcript with intron 9 inclusion, leading to a premature stop codon.
  • A deep intronic variant, c.1196+2681T>A, was found to cause pseudo-exon inclusion of intron 9.
  • This variant segregated with the disease phenotype in the affected family members.

Conclusions:

  • Deep intronic variants in PCSK1 can cause PC1/3 deficiency through aberrant splicing, leading to a characteristic polyendocrinopathy.
  • The phenotype of PC1/3 deficiency may necessitate extended genetic testing beyond standard exome sequencing for accurate diagnosis.
  • Timely diagnosis of PC1/3 deficiency is crucial and may require advanced genetic analyses to detect non-coding variants affecting splicing.