Mutations

PSEN1 L381F

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73683845 C>T
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CTT to TTT
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 11

Findings

This mutation was identified by whole exome sequencing in a family with suspected autosomal-dominant Kufs disease (adult-onset neuronal ceroid lipofuscinoses). Five affected individuals were described over three generations. The mutation was found to segregate with disease in all available family members (three individuals). The mutation was not present in 6,500 exomes available in the Exome Variant Server (EVS) database, supporting a role in pathogenicity.

The proband developed progressive dementia and ataxia at the age of 32. His fine motor coordination became impaired and he developed remote memory deficits. He developed slurred speech and an unsteady gait. Later he developed spastic paraparesis and died at age 36 from aspiration pneumonia. A skin biopsy showed lipofuscin containing phagocytic cells suggestive of neuronal ceroid lipofuscinoses, but his neuropathology was consistent with AD. The proband had two affected brothers with similar disease manifestations (onset at ages 29 and 30) and an affected father with onset at age 28 (Dolzhanskaya et al., 2014).

Neuropathology

Neuropathology consistent with AD, including neuritic amyloid plaques and neurofibrillary tangles. Hirano bodies and granulovacuolar degeneration were noted in the hippocampus (Dolzhanskaya et al., 2014).

Biological Effect

Although the biological effect of this mutation is unknown, in silico analysis indicated that it may affect the folding free energy and flexibility of the presenilin-1 protein (Dolzhanskaya et al., 2014). Moreover, a cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates that L381 forms part of one of two PSEN1 β-strands induced by APP binding. These strands, together with an APP β-strand, form a hybrid, three-stranded β–sheet that appears to be indispensable for APP cleavage (Zhou et al., 2019; Jan 2019 news).

Last Updated: 10 Aug 2019

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References

News Citations

  1. CryoEM γ-Secretase Structures Nail APP, Notch Binding

Paper Citations

  1. . A novel p.Leu(381)Phe mutation in presenilin 1 is associated with very early onset and unusually fast progressing dementia as well as lysosomal inclusions typically seen in Kufs disease. J Alzheimers Dis. 2014;39(1):23-7. PubMed.
  2. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.

External Citations

  1. Exome Variant Server (EVS)

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . A novel p.Leu(381)Phe mutation in presenilin 1 is associated with very early onset and unusually fast progressing dementia as well as lysosomal inclusions typically seen in Kufs disease. J Alzheimers Dis. 2014;39(1):23-7. PubMed.

Other mutations at this position

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