PSEN1 P242Lfs


Pathogenicity: Familial Acne Inversa : Not Classified
Clinical Phenotype: Familial Acne Inversa
Reference Assembly: GRCh37/hg19
Position: Chr14:73659528 C>-
Coding/Non-Coding: Coding
Mutation Type: Deletion
Codon Change: CCT to CTG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7


This mutation is a deletion of one of three cytosines, the third nucleotide in codon L241 or one of the first two nucleotides in codon P242 (Wang et al., 2010). The deletion results in a substitution of a leucine for a proline at position 242 and generates a premature stop codon within 15 nucleotides of the downstream exon 7/exon 8 boundary.

The mutation was identified using a combined genome-wide linkage scan and haplotype analysis of six large Han Chinese families who suffered from familial acne inversa, a chronic inflammatory disease of hair follicles. The disorder is characterized by draining sinuses, painful skin abscesses, and disfiguring scars. The family in which the P242Lfs mutation was found spanned three generations, including four affected individuals, all of whom carried the mutation. The mutation was absent from seven unaffected members.

As of 2010, no AD case had been reported to co-occur with acne inversa.

Not applicable.

Biological Effect
This mutation causes decreased levels of PSEN1 mRNA in lymphocytes, likely due to nonsense-mediated decay (Wang et al., 2010). However, the mutation potentially lies too close to the exon–exon junction for this type of degradation to be completely effective and, indeed, low levels of the mutated transcript are observed in patient lymphocytes (Newman et al., 2013). The resulting truncated protein is predicted to have a markedly altered three-dimensional structure (Li et al., 2019). Moreover, several in silico algorithms predicted it is damaging (Xiao et al., 2021).

Interestingly, the mutation appears to have no effect on cleavage of Appa, a zebrafish paralogue of human APP, but enhances Notch signaling (Newman et al., 2013).  Moreover, it enhances cytokine and chemokine expression and prolongs TNF- α production in human monocytes and macrophages activated with lipopolysaccharide (Li et al., 2019).

Last Updated: 11 Sep 2021


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Paper Citations

  1. . Gamma-secretase gene mutations in familial acne inversa. Science. 2010 Nov 19;330(6007):1065. PubMed.
  2. . Differential, dominant activation and inhibition of Notch signalling and APP cleavage by truncations of PSEN1 in human disease. Hum Mol Genet. 2013 Oct 6; PubMed.
  3. . Analysis of hidradenitis suppurativa-linked mutations in four genes and the effects of PSEN1-P242LfsX11 on cytokine and chemokine expression in macrophages. Hum Mol Genet. 2019 Apr 1;28(7):1173-1182. PubMed.
  4. . APP, PSEN1, and PSEN2 Variants in Alzheimer's Disease: Systematic Re-evaluation According to ACMG Guidelines. Front Aging Neurosci. 2021;13:695808. Epub 2021 Jun 18 PubMed.

Further Reading

No Available Further Reading

Protein Diagram

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