Strong association of the Saitohin gene Q7 variant with progressive supranuclear palsy
Citation Manager Formats
Make Comment
See Comments

Abstract
Recent reports are inconclusive in showing that the Q7R polymorphism of the novel Saitohin gene, nested in intron 9 of the tau gene, is associated with AD. The authors show that this polymorphism is in complete linkage disequilibrium with the extended tau H1/H2 haplotype and that the Q variant and QQ genotype of Q7R are strongly associated with progressive supranuclear palsy, implicating it as a possibly important pathogenic candidate.
The novel Saitohin (STH) gene, nested within intron 9 of the tau gene (MAPT) on chromosome 17q,1 codes for a 128-amino acid protein of unknown homologies and an expression profile resembling that of tau.1 Missense and splice-site mutations of MAPT cause frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP17).2 Although other related tauopathies, including Alzheimer disease (AD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD), are defined by neuropathologic lesions containing insoluble filamentous deposits of tau protein, mutations in MAPT are not known to cause these diseases. However, the H1 haplotype, which includes MAPT, has a strong genetic association with PSP and CBD.3 This haplotype is made up of several polymorphisms that span MAPT (∼130 kb) and flanking regions. The causative polymorphism in this haplotype remains elusive; no pathogenic coding or splice site mutations in MAPT have been directly implicated in PSP other than an R5L substitution in an isolated sporadic case.4 It is possible that hitherto unidentified polymorphic variants linked to the H1 haplotype could affect MAPT splicing, expression, or transcript stability. For example, single nucleotide polymorphisms found in the core promoter region of MAPT5 could affect transcription of the gene. Although neuropathologic evidence strongly supports MAPT dysfunction, it is also possible that the causative variant in the H1 haplotype affects another gene within this haplotype, in linkage disequilibrium (LD) with MAPT. An a224g coding polymorphism in STH causes a glutamine (Q) to arginine (R) substitution at residue 7 (Q7R).1 The R variant of this polymorphism and RR genotype are genetically associated with AD.1 We investigated this polymorphism in PSP and in relation to the H1/H2 haplotypes in a well-characterized case-control group.
Patients and methods.
The sample population consisted of 49 patients with PSP and 62 control subjects. As previously described, the PSP cases were either pathologically confirmed, clinically typical PSP cases (n = 20), or met modified clinical diagnostic criteria for National Institute of Neurological Disorders and Stroke probable PSP (n = 29).6 Although prominent early postural instability was used as a positive inclusion criterion, falls in the first symptomatic year were not considered mandatory and diagnostic exclusion criteria were applied as available from case notes. Pathologic confirmation of the diagnosis of PSP was made following standardized criteria.6 Normal controls from a European Brain Bank series had neither clinical evidence of neurodegenerative disease nor abnormal histopathology (average age at death of 72 years). The study population was primarily of white origin from Britain and western Europe. This work was approved by the Joint Medical Ethics Committee of the National Hospital of Neurology and Neurosurgery.
Tau haplotype was unambiguously determined as previously described3 by analysis of the presence of the 238-bp intron 9 deletion of the H2 haplotype (figure 1).
Figure 1. Representation of intron 9 of the tau gene (MAPT), showing relative distances (kb = kilobase pairs) of Saitohin gene (STH) coding sequence (CDS) from MAPT exons 9 and 10. Arrowhead over STH gene indicates direction of transcription. The relative position of the intron 9 deletion found in the H2 haplotype is indicated.
The STH gene was amplified with PCR primers FF-Cel 2: 5′-CCAAGTTCAGTTGCCATCTCC-3′ and OR Cel 2: 5′-CTCT-TGTGCATGGACCCTGTA-3′ flanking the STH coding sequence and the STH a → g polymorphism was analyzed after HinFI digestion (figure 2).1 Four random samples were sequenced in order to ensure accuracy of interpretation. We also sequenced the STH coding sequence of three pathologically confirmed, clinically typical PSP cases and three control samples that are H1/H1 homozygous in order to establish whether PSP cases carried any unique causative polymorphisms on the H1 backbone that were absent in unaffected controls. Statistical tests for Hardy-Weinberg equilibrium (HWE) were carried out by standard Pearson χ2 tests. Tests for genetic association were carried out by Fisher exact test (QR and RR genotypes were combined in the genotype test). The test for LD was carried out by likelihood ratio testing of haplotype frequencies inferred assuming LD (using EM estimation) against haplotype frequencies inferred assuming no LD.
Figure 2. Restriction enzyme analysis of Saitohin Q7R polymorphism. PCR products of the Q allele have four HinFI restriction sites resulting in five fragments (261, 243, 194, 54, and 38 bp). The R allele creates a new HinFI site, cutting the 194 bp fragment into two 97 bp fragments. The 54 and 38 bp fragments are not shown.
Results.
Automated sequence analysis of three pathologically confirmed clinically typical PSP cases and three unaffected controls homozygous for the H1 haplotype showed the absence of any pathogenic sequence variants of STH that belonged to the H1 haplotype, that exclusively segregates with the disorder. All six samples were homozygous for the Q variant, indicating that it predicts the H1 haplotype, as was further confirmed in the case-control study. There was no departure from HWE in the PSP (χ2 = 0.0213, df = 1, p = 0.8841) and control (χ2 = 1.7494, df = 1, p = 0.186) groups. The H2/H2, H2/H1, and H1/H1 genotypes associated perfectly with the RR, QR, and QQ genotypes. The inferred LD between the two loci appeared to be complete (χ2 = 94.08, df = 1, p = 3 × 10−22). Haplotype and genotype counts in PSP cases and controls are given in the table: comparison of allele frequencies shows that the Q variant and QQ genotype are considerably enriched in PSP (test for allelic association in all cases: p = 9 × 10−6; test for genotypic association: p = 4 × 10−6).
Table Genotype and haplotype frequencies of the Saitohin Q7R polymorphism in PSP
Discussion.
We have shown that the STH Q7R polymorphism appears to be in complete LD with the extended MAPT H1/H2 haplotype, with the geno-type state for STH completely predicting that of the MAPT haplotype. By definition, this extends the well-established association of the MAPT haplotype with PSP and CBD to STH and implicates the Q allele of this non-silent STH polymorphism as a potentially important candidate pathogenic variant in four-repeat tauopathies. However, the Q allele (H1 haplotype) is also the most common haplotype in the normal controls. This implies that there should be unfavorable interactions with other genetic or environmental risk factors or that the actual culprit variation that is unique to the H1 haplotype remains undiscovered. It would therefore be important to continue the search for H1-specific variations between epidemiologically matched case-control groups.
The strong LD and association are not surprising because the STH gene is nested between exons 9 and 10 of MAPT1 (see figure 1). Noting the complete LD between the STH Q7R polymorphism and the extended MAPT H1/H2 haplotypes, the observation of an association of the R allele and RR genotype with AD1 should apply to the entire H2 haplotype of the MAPT locus. However, several studies have failed to consistently confirm an association of the MAPT haplotype with AD (see references in reference 8), at best only implicating the MAPT locus as a weak risk factor in AD.7 More recently, three separate groups failed to show significant associations of the STH Q7R polymorphism with AD in much larger case-control groups.7-9⇓⇓ It is interesting that these studies with AD are not consistent. Because the STH Q7R polymorphism is part of the MAPT H1/H2 haplotypes, these differences in association that are observed in AD are not likely to be due to differences in LD.
The significance of the Q7R polymorphism remains to be elucidated. The STH gene codes for a protein of unknown homologies and function but has an expression profile similar to that of MAPT. A tantalizing possibility is the hypothesis proposing a functional relationship between tau and Saitohin based on parallels from the choline acetyltransferase (ChAT)/vesicular acetylcholine transporter (VAChT) locus.1 The VAChT gene is nested in the first intron of the ChAT gene and both genes are required for expression of the cholinergic phenotype and could be coregulated.10 Saitohin may play a similarly important role in tau regulation, and the Q7R polymorphism may cause a defect in this role, causing a predisposition to pathogenesis of PSP and CBD.
Acknowledgments
Supported by the Reta Lila Weston Trust, the PSP (Europe) Association, and the PD Society.
- Received December 17, 2002.
- Accepted in final form March 27, 2003.
References
- ↵Conrad C, Vianna C, Freeman M, Davies P. A polymorphic gene nested within an intron of the tau gene: implications for Alzheimer’s disease. Proc Natl Acad Sci USA . 2002; 99: 7751–7756.
- ↵Hutton M. Missense and splice site mutations in tau associated with FTDP-17: multiple pathogenic mechanisms. Neurology . 2001; 56 (suppl 4): S21–25.
- ↵Baker M, Litvan I, Houlden H, et al. Association of an extended haplotype in the tau gene with progressive supranuclear palsy. Hum Mol Genet . 1999; 8: 711–715.
- ↵
- ↵
- ↵Morris HR, Janssen JC, Bandmann O, et al. The tau gene A0 polymorphism in progressive supranuclear palsy and related neurodegenerative diseases. J Neurol Neurosurg Psychiatry . 1999; 66: 665–667.
- ↵
- ↵
- ↵Streffer JR, Papassotiropoulos A, Kurosinski P, et al. Saitohin gene is not associated with Alzheimer’s disease. J Neurol Neurosurg Psychiatry . 2003; 74: 362–363.
- ↵
Letters: Rapid online correspondence
REQUIREMENTS
You must ensure that your Disclosures have been updated within the previous six months. Please go to our Submission Site to add or update your Disclosure information.
Your co-authors must send a completed Publishing Agreement Form to Neurology Staff (not necessary for the lead/corresponding author as the form below will suffice) before you upload your comment.
If you are responding to a comment that was written about an article you originally authored:
You (and co-authors) do not need to fill out forms or check disclosures as author forms are still valid
and apply to letter.
Submission specifications:
- Submissions must be < 200 words with < 5 references. Reference 1 must be the article on which you are commenting.
- Submissions should not have more than 5 authors. (Exception: original author replies can include all original authors of the article)
- Submit only on articles published within 6 months of issue date.
- Do not be redundant. Read any comments already posted on the article prior to submission.
- Submitted comments are subject to editing and editor review prior to posting.
You May Also be Interested in
Dr. Babak Hooshmand and Dr. David Smith
► Watch
Related Articles
- No related articles found.
Alert Me
Recommended articles
-
Articles
Haplotypes and gene expression implicate the MAPT region for Parkinson diseaseThe GenePD StudyJ. E. Tobin, J. C. Latourelle, M. F. Lew et al.Neurology, May 28, 2008 -
Views And Reviews
Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome)Report of the NINDS-SPSP International Workshop*I. Litvan, Y. Agid, D. Calne et al.Neurology, July 01, 1996 -
ARTICLES
Accuracy of clinical criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome)I. Litvan, Y. Agid, J. Jankovic et al.Neurology, April 01, 1996 -
Article
HLA and microtubule-associated protein tau H1 haplotype associations in anti-IgLON5 diseaseCarles Gaig, Guadalupe Ercilla, Xavier Daura et al.Neurology: Neuroimmunology & Neuroinflammation, August 12, 2019