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A novel mutation of PCSK1 responsible for PC1/3 deficiency in two siblings

Rémi Duclaux-Loras1, Patrice Bourgeois2, Pierre-Marie Lavrut3

  • 1Hospices Civils de Lyon, Hôpital Femme Mère Enfant, Service de Gastroentérologie, Hépathologie et Nutrition Pédiatrique, Bron, France; INSERM U1111, Centre International de Recherche en Infectiologie, Lyon, France.

Clinics and Research in Hepatology and Gastroenterology
|March 4, 2021
PubMed

Insights

Proprotein convertase 1 (PCSK1) deficiency causes severe neonatal diarrhea and hormonal issues due to impaired prohormone processing. This study details two siblings with a novel PCSK1 mutation, highlighting the need for early intervention and supportive care.

Area of Science:

  • Genetics
  • Endocrinology
  • Gastroenterology

Background:

  • Proprotein convertase 1 (PCSK1) deficiency is a rare genetic disorder impacting prohormone processing.
  • It leads to malabsorptive diarrhea and multiple endocrinopathies, with only 26 cases previously reported.
  • Proper processing of prohormones like proinsulin is crucial for normal physiological function.

Observation:

  • Two siblings presented with severe congenital diarrhea, central diabetes insipidus, growth hormone deficiency, and hypoadrenalism.
  • Next-generation sequencing identified a homozygous missense mutation (c.500A>C, p.Asp167Ala) in the PCSK1 gene's catalytic domain.
  • Both patients exhibited elevated proinsulin levels, indicative of processing defects.

Findings:

  • The identified homozygous missense mutation in PCSK1 is associated with severe clinical manifestations.
  • Patients required intensive management including parenteral nutrition and hormone replacement therapy from early life.
  • Recurrent infections and septic shocks were significant complications in the affected siblings.

Implications:

  • This case expands the known spectrum of PCSK1 mutations and their clinical consequences.
  • Understanding PCSK1's role in prohormone processing is vital for diagnosing and managing related disorders.
  • Early diagnosis and comprehensive management, including nutritional and hormonal support, are critical for improving outcomes in PCSK1 deficiency.

Keywords:
Congenital chronic diarrhoeaMonogenic disordersPCSK1TNGS

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