Mutations

MAPT N296del (ΔN296)

Overview

Pathogenicity: Other Tauopathy : Pathogenic, Frontotemporal Dementia : Not Pathogenic
Clinical Phenotype: Progressive Supranuclear Palsy
Genomic Mutation Name (MET1):
Genomic Mutation Name (NT1):
dbSNP ID: rs63751392
Coding/Non-Coding: Coding
Genomic Region: Exon 10
Mutation Type: Deletion
Codon Change: ATA to -

Findings

This deletion mutation was originally identified in a Spanish kindred in which two brothers were affected with atypical progressive supranuclear palsy (PSP). A homozygous deletion at codon 296 (N296del) was identified in one of the brothers. In heterozygous individuals, this mutation is incompletely penetrant and is associated with a phenotype similar to idiopathic Parkinson's disease (PD) (Pastor et al., 2001).

A second N296del family with a similarly complicated mode of inheritance has been described (Rossi et al., 2004; see also Oliva et al., 2004). The proband was 36 years old when he developed symptoms of a PSP-like syndrome. He developed antecollis (forward flexion of the head and neck), dysarthria (difficulty speaking due to muscular impairment), postural instability with falls, and slowing of ocular movements. Although neither parent was affected, three siblings of the proband's father had significant neurological conditions. A paternal uncle developed an atypical parkinsonism at age 51 with resting tremor, rigidity, pyramidal signs, and cognitive impairment. His symptoms were unresponsive to L-dopa and he died nine years after symptom onset. A paternal aunt developed PD at age 63. Her symptoms were responsive to L-dopa. A second paternal uncle reportedly died from ALS. The proband was found to carry a heterozygous deletion, as did the aunt with PD, two asymptomatic sisters of the proband, and three asymptomatic cousins of the proband (daughters of the uncle with atypical parkinsonism). Segregation with disease could not be established and reduced penetrance was suspected.

Neuropathology

In the Spanish proband, atrophy of the right precentral gyrus and the brainstem were observed, as well as neuron loss and gliosis in the substantia nigra, several brainstem nuclei, and diencephalon. Hyperphosphorylated tau and neurofibrillary tangles were noted in neurons from many brain regions. Accumulated tau was also observed in astrocytes and oligodendrocytes (Ferrer et al., 2003).

Biological Effect

The N296del mutation decreases the ability of 4-repeat tau to promote microtubule assembly and increases the aggregation of the protein in vitro. A variable effect on exon 10 splicing has been observed, but appears to be a minor contributer to overall dysfunction (Grover et al., 2002; Yoshida et al., 2002).

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References

Paper Citations

  1. . Familial atypical progressive supranuclear palsy associated with homozigosity for the delN296 mutation in the tau gene. Ann Neurol. 2001 Feb;49(2):263-7. PubMed.
  2. . Progressive supranuclear palsy and Parkinson's disease in a family with a new mutation in the tau gene. Ann Neurol. 2004 Mar;55(3):448. PubMed.
  3. . Tau gene delN296 mutation, Parkinson's disease, and atypical supranuclear palsy. Ann Neurol. 2004 Mar;55(3):448-9. PubMed.
  4. . Tau phosphorylation and kinase activation in familial tauopathy linked to deln296 mutation. Neuropathol Appl Neurobiol. 2003 Feb;29(1):23-34. PubMed.
  5. . Effects on splicing and protein function of three mutations in codon N296 of tau in vitro. Neurosci Lett. 2002 Apr 19;323(1):33-6. PubMed.
  6. . Functional effects of tau gene mutations deltaN296 and N296H. J Neurochem. 2002 Feb;80(3):548-51. PubMed.

Further Reading

Papers

  1. . Functional effects of tau gene mutations deltaN296 and N296H. J Neurochem. 2002 Feb;80(3):548-51. PubMed.

Learn More

Alzheimer Disease & Frontotemporal Dementia Mutation Database

Primary Papers

  1. . Familial atypical progressive supranuclear palsy associated with homozigosity for the delN296 mutation in the tau gene. Ann Neurol. 2001 Feb;49(2):263-7. PubMed.

Other mutations at this position

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