Overview

Pathogenicity: Other Tauopathy : Pathogenic, Parkinson's Disease : Not Classified
Clinical Phenotype: Progressive Supranuclear Palsy, Parkinson's Disease
Position: (GRCh38/hg38):Chr17:46010373_46010375 AAT>---
Position: (GRCh37/hg19):Chr17:44087739_44087741 AAT>---
dbSNP ID: rs63751392
Coding/Non-Coding: Coding
DNA Change: Deletion
Expected RNA Consequence: Deletion
Expected Protein Consequence: Deletion
Codon Change: AAT to ---
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 10

Findings

This trinucleotide deletion mutation was first identified in a Spanish family in which individuals across two generations were affected by either Parkinson's disease or atypical progressive supranuclear palsy. Notably, in addition to several heterozygous carriers, one family member was homozygous for the deletion due to a consanguineous marriage. Due to the limited information available, it is unclear whether the deletion segregates with disease or if the specific genotype (i.e., homozygous vs. heterozygous) affects the clinical phenotype. The reported pedigree shows two brothers affected by PSP; one homozygous for the deletion and one with an unknown genotype. Two uncles were affected by PD at ages 62 and 71; both were heterozygous carriers. A handful of other family members were also heterozygous for the deletion, but unaffected, suggesting incomplete penetrance, at least in the heterozygous state (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

This mutation involves the deletion of three nucleotides, resulting in a predicted protein sequence lacking asparagine (N) at position 296. Because the deletion is in-frame, the remainder of the protein sequence would be intact. In vitro, the N296del mutation decreases the ability of 4-repeat tau to promote microtubule assembly. It also increases tau aggregation in vitro. In contrast to the other mutations affecting codon 296, it appears to have little or no effect on exon 10 splicing (Grover et al., 2002; Yoshida et al., 2002).

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References

Paper Citations

1. Pastor P, Pastor E, Carnero C, Vela R, García T, Amer G, Tolosa E, Oliva R. 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. Rossi G, Gasparoli E, Pasquali C, Di Fede G, Testa D, Albanese A, Bracco F, Tagliavini F. 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. Oliva R, Pastor P. Tau gene delN296 mutation, Parkinson's disease, and atypical supranuclear palsy. Ann Neurol. 2004 Mar;55(3):448-9. PubMed.
4. Ferrer I, Pastor P, Rey MJ, Muñoz E, Puig B, Pastor E, Oliva R, Tolosa E. Tau phosphorylation and kinase activation in familial tauopathy linked to deln296 mutation. Neuropathol Appl Neurobiol. 2003 Feb;29(1):23-34. PubMed.
5. Grover A, DeTure M, Yen SH, Hutton M. 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. Yoshida H, Crowther RA, Goedert M. Functional effects of tau gene mutations deltaN296 and N296H. J Neurochem. 2002 Feb;80(3):548-51. PubMed.

Further Reading

Learn More

1. Alzheimer Disease & Frontotemporal Dementia Mutation Database