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Pathogenic deep intronic PCSK1 variant causes proprotein convertase 1/3 deficiency in a family: short report

Proprotein convertase 1/3 (PC1/3), encoded by PCSK1, is expressed in neuronal and endocrine cell types, where it activates a number of protein precursors that play roles in energy homeostasis. Biallelic PCSK1 loss-of-function mutations cause a polyendocrinopathy; a total of 34 patients were reported...

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Main Authors: Huber, Leah M. (Author) , Subaşıoğlu, Aslı (Author) , Garczarczyk-Asim, Dorota (Author) , Valovka, Taras (Author) , Müller, Thomas (Author) , Adam, Rüdiger (Author) , Janecke, Andreas R. (Author)
Format: Article (Journal)
Language:English
Published: July 2025
In: Clinical genetics
Year: 2025, Volume: 108, Issue: 1, Pages: 102-106
ISSN:1399-0004
DOI:10.1111/cge.14717
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1111/cge.14717
Verlag, kostenfrei, Volltext: http://onlinelibrary.wiley.com/doi/abs/10.1111/cge.14717
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Author Notes:Leah M. Huber, Aslı Subaşıoğlu, Dorota Garczarczyk-Asim, Taras Valovka, Thomas Müller, Rüdiger Adam, Andreas R. Janecke
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Summary:Proprotein convertase 1/3 (PC1/3), encoded by PCSK1, is expressed in neuronal and endocrine cell types, where it activates a number of protein precursors that play roles in energy homeostasis. Biallelic PCSK1 loss-of-function mutations cause a polyendocrinopathy; a total of 34 patients were reported. An infant with congenital malabsorptive diarrhea of all carbohydrates underwent exome sequencing (ES), with particular consideration of PC1/3 deficiency, but no mutations were found. The onset of obesity in the second year of life increased suspicion of PC1/3 deficiency in the proband, as well as in his equally affected cousin. Transcript analysis revealed minor amounts of an aberrant PCSK1 transcript containing intron 9 sequence and encoding a premature stop codon (p.Pro400Valfs*35). A deep intronic PCSK1 variant, NG_021161.1(NM_000439.5):c.1196+2681T>A, was found to segregate in the proband's family with the disease. A minigene approach demonstrated that the identified deep-intronic variant underlies pseudo-exon inclusion of the intron 9 sequence in the transcript. The characteristic phenotype of PC1/3 deficiency might require extended genetic testing to make a timely diagnosis.
Item Description:Erstmals veröffentlicht: 1. Februar 2025
Gesehen am 14.07.2025
Physical Description:Online Resource
ISSN:1399-0004
DOI:10.1111/cge.14717

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