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GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Diagnosis/testing. The clinical diagnosis of FTDP-17 is supported by the presence of dementia and/or parkinsonism, frontal and/or temporal atrophy on neuroimaging, and dementia and/or parkinsonism in two or more first-degree relatives consistent with an autosomal dominant mode of inheritance. Computed tomography (CT) or magnetic resonance imaging (MRI) reveals cortical atrophy and ventricular enlargement that may be symmetrical or asymmetrical; severity increases over time. Single photon emission computed tomography (SPECT) shows decreased cerebral perfusion anteriorly that is present early in the disease, preceding CT or MRI findings. Molecular genetic testing of the microtubule-associated protein tau (MAPT) gene is available on a clinical basis. In research studies, between 25% and 40% of families with autosomal dominant frontotemporal dementia show mutations in MAPT.
Management. Sedative or antipsychotic drugs reduce extreme restlessness, roaming behavior, delusions, and hallucinations. Individuals with seizures are treated with anti-epileptic drugs; levodopa treatment may benefit some individuals with parkinsonian signs.
Genetic counseling. FTDP-17 is inherited in an autosomal dominant manner. Most individuals diagnosed with FTDP-17 are offspring of a person with the clinical features of frontotemporal dementia and/or parkinsonism; however, because of the late onset and relatively rapid course of the disease, the affected parent often dies before onset of the disease in the offspring. Because most probands have an affected parent, most sibs of a proband are at 50% risk of having FTDP-17. The risk to offspring of an affected individual is 50%. Prenatal testing for FTDP-17 for fetuses at risk is available when the disease-causing MAPT mutation has been identified in an affected family member.
The diagnosis of FTDP-17 is supported by the presence of the following [Lund et al 1994, Neary et al 1998]:
Frontotemporal dementia and/or parkinsonism
Frontal and/or temporal atrophy on neuroimaging:
Computed tomography (CT) or magnetic resonance imaging (MRI) may be initially normal. Cortical atrophy and ventricular enlargement may be symmetrical or asymmetrical; severity increases over time [Foster et al 1997, van Swieten et al 1999].
Single photon emission computed tomography (SPECT) shows decreased cerebral perfusion anteriorly that is present early in the disease, preceding CT or MRI findings.
Striatal uptake of [18F]Fluoro-L-dopa is reduced in individuals with early parkinsonism [Wszolek et al 1992].
Family history of dementia and/or parkinsonism in two or more first-degree relatives consistent with an autosomal dominant mode of inheritance
Neuropathology showing intraneuronal deposition of hyperphosphorylated tau protein demonstrated by phosphorylation-dependent anti-tau antibodies. The specific type of deposits is mutation dependent. Tau pathology consists of abundant neurofibrillary tangles in the hippocampus, cortical regions, and subcortical nuclei in some individuals and pretangle type of deposits in neurons and glial cells in most individuals.
The definitive diagnosis of FTDP-17 relies upon demonstration of a disease-causing mutation in the MAPT (tau) gene or through a research protocol that documents linkage to chromosome 17q.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Gene. MAPT is the only gene known to be associated with frontotemporal dementia with parkinsonism linked to chromosome 17.
Other loci. In some families with frontotemporal dementia showing evidence of linkage to chromosome 17q21.1, neither mutations in the MAPT gene nor tau pathology at neuropathologic examination has been found. The disease in these families is caused either by a mutation in another gene localized in the same genomic region or by an undetected MAPT mutation [Froelich Fabre et al 2003, Lendon et al 1998, Rosso et al 2001, Rademakers et al 2002, Wilhelmsen et al 2004]
Clinical uses
Clinical testing
Targeted mutation analysis. Testing is clinically available for three mutations: p.Pro301Leu, p.Ala279Leu, and a splice isoform mutation that changes C to T at position 14 of IVS 10. The detection rate using this panel is not known.
Sequence analysis of select gene regions. Sequence analysis of exon 10 and the flanking intron regions can be used to detect the three mutations described above as well as other mutations in this region.
Sequence analysis. Sequence analysis of MAPT is available on a clinical basis for individuals with frontotemporal dementia who have a positive family history of dementia. Between 25% and 40% of families with autosomal dominant frontotemporal dementia show mutations in MAPT. Most mutations are localized in exons 9 through 13. Additional mutations are present in the 5' part of the intron following exon 10. The only mutations that have been found in exon 1 are p.Arg5His [Hayashi et al 2002] and p.Arg5Leu [Poorkaj et al 2002].
Note: (1) Mutations in MAPT are rare in simplex cases of frontotemporal dementia (i.e., a single occurrence in a family) [Houlden et al 1999, Rizzu et al 1999, Poorkaj et al 2001, Stanford et al 2000], with frequencies ranging from zero to four percent of individuals in population-based samples. (2) The occurrence of de novo mutations was recently confirmed by Boeve et al (2005).
| Test Methods | Mutations Detected | Mutation Detection Frequency 1 | Test Availability |
|---|---|---|---|
| Targeted mutation analysis | p.Pro301Leu, p.Ala279Leu, splice isoform mutation at position 14 of IVS 10 | Unknown | Clinical
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| Sequence analysis of select exons | Mutations in exon 10 and flanking intron regions 2 | ||
| Sequence analysis | MAPT gene mutations | 25%-40% |
Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.
Although MAPT mutations are mainly found in individuals with typical FTD, the identification of MAPT mutations in individuals with progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and dementia with epilepsy [Sperfeld et al 1999] has broadened the spectrum of clinical findings in FTDP-17. It has therefore been suggested that FTDP-17 is part of a larger spectrum that includes other tauopathies such as sporadic Pick's disease, PSP, and CBD [Kertesz 2003].
Clinical features of PSP were observed in individuals with the p.Ser305Ser mutation and an intron mutation at +11, and in homozygotes of the p.Asn296del mutation [Stanford et al 2000, Pastor et al 2001, Miyamoto et al 2001].
Mild, late-onset parkinsonism has been reported in heterozygotes with the p.Asn296del mutation [Pastor et al 2001].
In a few mutations, the clinical picture or pathologic features show resemblance with CBD [Bugiani et al 1999, Spillantini et al 2000].
FTDP-17 is a presenile dementia affecting the frontal and temporal cortex and some subcortical nuclei. Clinical presentation is variable. Affected individuals may present with slowly progressive behavioral changes, language disturbances, and/or extrapyramidal signs. Some present with rigidity, bradykinesia, supranuclear palsy, and saccadic eye movement disorders. Symptoms usually start between 40 and 60 years of age, but may occur earlier or later. Disease duration is usually between five and ten years, but occasionally may be as long as 20 to 30 years. The disease progresses over a few years into profound dementia with mutism.
Behavioral changes. Disinhibition and loss of initiative are the most common presenting symptoms. Affected individuals lose interest in their environment and neglect their personal hygiene. Obsessive-compulsive behavior and delusions or hallucinations are early clinical features in some individuals. Roaming, restlessness, verbal agressiveness, hyperorality including alcohol abuse, and financial mismanagement are frequently seen [Foster et al 1997, Bird et al 1999].
Psychiatric symptoms. Persecutory delusions and visual or auditory hallucinations can occur [Sumi et al 1992].
Cognitive decline. Word-finding difficulties and semantic paraphasias in conversational speech are common early findings. Orientation in time and place, visuoconstructive functions, and short-term memory remain intact initially. Executive functions, attention, concentration, and abstract reasoning ability become impaired in all affected individuals. Comprehension of language remains relatively preserved over the course of the disease. Perseveration, repetitive utterances, and echolalia lead to mutism after several years [Foster et al 1997].
Extrapyramidal signs. Parkinsonian signs may be the first manifestations of the disease, sometimes in conjunction with behavioral changes. Affected individuals show decreased facial expression, bradykinesia, postural instability, and rigidity without resting tremor. These extrapyramidal signs are unresponsive or only partially responsive to L-dopa treatment. Supranuclear palsy, poor saccadic eye movements, unilateral rigidity and dystonia, and alien hand syndrome are occasionally seen and are consistent with the clinical diagnosis of progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD) [Bugiani et al 1999, Stanford et al 2000, Morris et al 2003].
Epilepsy. Epileptic seizures usually do not occur in individuals with FTDP-17 except for those with the p.Pro301Ser mutation [Bugiani et al 1999, Sperfeld et al 1999].
Motor neuron disease. Some members of the family with frontotemporal dementia reported by Lynch et al (1994) and a person with the novel p.Lys317Met tau mutation reported by Zarranz et al (2005) had motor neuron disease consistent with the diagnosis of amyotrophic lateral sclerosis (ALS).
Headache. Affected individuals may complain about headache for years preceding the onset of the disease [Sperfeld et al 1999, van Swieten et al 1999].
Neuropathology. Aside from focal atrophy, the frontal and temporal lobes are macroscopically normal. Neuronal loss, gliosis, and spongiosis in the superficial cortical layers are seen on routine microscopic staining. Upon immunohistochemical analysis, all individuals with tau mutations show pathologic accumulation of hyperphosphorylated tau protein.
Clinical presentation and neuropathologic changes vary widely according to the localization of the mutations within MAPT. Some intrafamilial variation exists, suggesting that other genetic or environmental factors influence the disease process.
The p.Pro301Ser mutation is significantly associated with an early onset between 20 and 30 years of age [Lossos et al 2003] and the occurrence of epileptic seizures or myoclonus [Bugiani et al 1999, Sperfeld et al 1999].
A longer duration up to 20-30 years is associated with the p.Arg406Trp mutation [Ostojic et al 2004, Reed et al 1997, van Swieten et al 1999].
Early parkinsonism and progressive supranuclear palsy are mainly encountered in individuals with the splice donor site mutations p.Asn279Lys, p.Lys280del, and p.Ser305Ser; they have also been described with homozygosity for the p.Asn296del mutation [Delisle et al 1999, Stanford et al 2000, Pastor et al 2001, Soliveri et al 2003].
The localization of mutations in MAPT is associated with different morphology of tau filaments and composition of tau isoforms [Goedert et al 1999].
Neurofibrillary tangles (NFT) or tau-positive pretangles in neurons and tau deposits in glial cells are found in individuals with coding mutations in exons 9 and 10 and splice donor site mutations [Spillantini et al 1997; Spillantini, Crowther et al 1998]. Individuals with the p.Val337Met and p.Arg406Trp mutations (in exons 12 and 13) show NFT in the absence of glial inclusions [Reed et al 1998, van Swieten et al 1999].
Motor neuron disease occurred in a family with the exon 10 plus 14 mutation [Lynch et al 1994] and in the novel p.Lys317Met tau mutation [Zarranz et al 2005].
Psychosis has been noted in several families, especially the single kindred with the p.Val337Met mutation [Sumi et al 1992, Poorkaj et al 1998].
The p.Leu315Arg mutation has been identified in individuals with FTDP-17 as well as in their unaffected parents, suggesting non-penetrance for this mutation in some individuals [van Herpen et al 2003].
Homozygosity for the p.Asn296del mutation was found in a person with atypical progressive supranuclear palsy. Among the heterozygous individuals in this family, two with probable Parkinson disease were identified, but none of heterozygotes developed atypical parkinsonism [Pastor et al 2001].
No evidence for anticipation exists in FTDP-17.
The etiologic role of the tau gene was suspected for the first time when a family with so-called dementia-disinhibition-parkinsonism-amyotrophy complex (DDPAC) showed significant linkage to the tau gene-containing region on chromosome 17q21-22 [Wilhelmsen et al 1994]. Subsequently, this linkage was confirmed for several familial disorders known in the older literature under different terms, including hereditary Pick's disease, familial progressive subcortical gliosis, pallidopontonigral degeneration (PPND), hereditary dysphasic disinhibition dementia, and autosomal dominant dementia with widespread neurofibrillary tangles [Lanska et al 1994, Wijker et al 1996, Froelich et al 1997, Clark et al 1998, Lendon et al 1998].
The term frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) was proposed at the consensus meeting in Ann Arbor in 1996 in order to include the clinical and pathologic spectrum of 13 large families with significant linkage to chromosome 17q21-22 [Foster et al 1997].
The prevalence of FTDP-17 was estimated in a genetic-epidemiologic study in the Netherlands [Stevens et al 1998]. Between 1994 and 1998, fifteen individuals with FTDP-17 were ascertained in a population of 15 million [Rizzu et al 1999]. The frequency of MAPT mutations in a more recent study has proven to be higher than previously demonstrated, i.e., 34 out of 49 (70%) individuals with autosomal dominant inheritance, and 34 out of 105 (33%) individuals with a positive family history [Rosso et al 2002]. That the prevalence of FTDP-17 may be approximately 1.5 to 2 times higher is supported by observations that the disease may often go unrecognized. Mutations in MAPT are rare in affected individuals with no family history of frontotemporal dementia [Houlden et al 1999, Rizzu et al 1999, Poorkaj et al 2001], although a de novo mutation has been reported [Boeve et al 2005].
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Mutations in MAPT are not identified in 60% of individuals with frontotemporal dementia with a positive family history [Rizzu et al 1999].
In some families with frontotemporal dementia showing evidence of linkage to chromosome 17q21.1, neither mutations in the MAPT gene nor tau pathology at neuropathologic examination has been found. The disease in these families is caused either by a mutation in another gene localized in the same genomic region or by an undetected MAPT mutation [Lendon et al 1998, Rosso et al 2001, Rademakers et al 2002, Froelich Fabre et al 2003, Wilhelmsen et al 2004].
Other genes associated with frontotemporal dementia have been identified on chromosome 3 (endosomal ESCRTIII-complex subunit CHMP2B gene) [Skibinski et al 2005] and chromosome 9p21.1-p12 (valosin-containing protein gene) [Watts et al 2004].
Another hereditary form of frontotemporal dementia associated with amyotrophic lateral sclerosis has shown linkage to chromosome 9q21-q22 [Hosler et al 2000]; the gene has not yet been identified.
Other considerations. Structural imaging may show focal atrophy and may exclude other causes of dementia (e.g., frontal meningeoma, chronic subdural hematoma).
The diagnosis of Alzheimer disease should be considered in individuals with mild behavioral changes, prominent memory disturbance and loss of initiative, or word-finding problems in the absence of evident frontotemporal atrophy on neuroimaging.
Although FTDP-17 may present with parkinsonism, several other gene defects or loci have been identified for familial Parkinson disease (see Parkinson Disease Overview).
Progressive supranuclear palsy (PSP) is most often sporadic. An association between PSP and homozygosity for the A0 allele within the MAPT gene region has been reported and confirmed [Conrad et al 1997].
Other familial neurologic diseases associated with dementia or parkinsonian features also need to be considered, such as Huntington disease and dementia with Lewy bodies.
Non-genetic acquired causes of dementia should always be considered.
To establish the extent of disease in an individual diagnosed with frontotemporal dementia with parkinsonism-17 (FTDP-17), the following evaluations are recommended:
A structured general and family history, physical and neurologic examination
Evaluation of the extent and profile of cognitive disturbance by neuropsychological examination
Sedative or antipsychotic drugs help to reduce extreme restlessness, roaming behavior, delusions, and hallucinations.
Individuals with seizures are treated with anti-epileptic drugs.
Levodopa treatment may benefit some individuals with parkinsonian signs [Wszolek et al 1992].
Behavorial changes and the loss of insight and judgment in individuals with FTDP-17 often present a considerable burden for partners or other caregivers. Information about the disease and psychological support for partners or other caregivers is essential.
A recent clinical trial with the selective serotonin reuptake inhibitor (SSRI) paroxetine showed an increase in cognitive impairment in persons treated with this drug [Deakin et al 2004]. Conversely, a previous study with another SSRI, trazodone, showed a favorable effect on behavioral disturbances and agitation without cognitive decline [Lebert et al 2004]. Further studies are needed to clarify this issue.
In persons with FTD in general, one phase II study is investigating the effect of direct current (DC) electrical polarization of the brain on frontal dysfunction and another clinical study is investigating the effects of a stimulant (dextroamphetamine) and an atypical antipsychotic (quetiapine) on behavioral symptoms. (See ClinicalTrials.gov for more information on FTD studies and on clinical studies for other disorders and conditions.)
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
FTDP-17 is inherited in an autosomal dominant manner.
Parents of a proband
Most individuals diagnosed with FTDP-17 have had an affected parent with the clinical features of frontotemporal dementia and/or parkinsonism; however, because of the late onset and relatively rapid course of the disease, the affected parent has often died before onset of the disease in the offspring.
A proband with FTDP-17 may have the disorder as the result of a de novo gene mutation. The proportion of cases caused by de novo mutations is extremely low.
Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include molecular genetic testing of MAPT.
Note: Although most individuals diagnosed with FTDP-17 have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, incomplete penetrance, or late onset of the disease in the affected parent.
Sibs of a proband
The risk to the sibs of the proband depends upon the genetic status of the proband's parents.
If a parent of the proband was affected or had a disease-causing allele, the risk to the sibs of inheriting the allele is 50%. Because some mutations (e.g., p.Leu315fArg) show reduced penetrance, some individuals who inherit a disease-causing allele may not manifest symptoms.
When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low. If neither parent of the proband has a MAPT mutation detectable in DNA from leukocytes, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband. One instance of possible germline mosaicism was reported by Boeve et al (2005), who determined that neither parent of two affected sibs was heterozygous for their MAPT mutation.
Offspring of a proband. Each child of an individual with FTDP-17 is at a 50% risk of inheriting the mutation.
Other family members of a proband. The risk to other family members depends upon the status of the proband's parents. If a parent is found to have been affected, his or her family members are at risk.
Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or undisclosed adoption could also be explored.
Family planning. The optimal time for the determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
DNA banking. DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See DNA Banking for a list of laboratories offering this service.
Testing of at-risk asymptomatic adults. Testing of at-risk asymptomatic adults for FTDP-17 is available according to the principles described in Molecular Genetic Testing. This testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals. When testing at-risk individuals for FTDP-17, an affected family member should be tested first to confirm that the disorder in the family is actually FTDP-17.
Testing for the disease-causing mutation in the absence of definite symptoms of the disease is predictive testing. At-risk asymptomatic adult family members may seek testing in order to make personal decisions regarding reproduction, financial matters, and career planning. Others may have different motivations including simply the "need to know." Testing of asymptomatic at-risk adult family members usually involves pretest interviews in which the motives for requesting the test, the individual's knowledge of FTDP-17, the possible impact of positive and negative test results, and bone and neurologic status are assessed. Those seeking testing should be counseled about possible problemsthat they may encounter with regard to health, life, and disability insurance coverage, employment and educational discrimination, and changes in social and family interaction. Other issues to consider are implications for the at-risk status of other family members. Informed consent should be procured and records kept confidential. Individuals with a positive test result need arrangements for long-term follow-up and evaluations.
Testing of at-risk asymptomatic individuals during childhood. Consensus holds that at-risk asymptomatic individuals younger than 18 years of age should not have testing. The principal arguments against testing asymptomatic individuals during childhood are that it removes their choice to know or not know this information, it raises the possibility of stigmatization within the family and in other social settings, and it could have serious educational and career implications [Bloch & Hayden 1990, Harper & Clarke 1990]. (See also the National Society of Genetic Counselors resolution on genetic testing of children and the American Society of Human Genetics and American College of Medical Genetics points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents.)
Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15-18 weeks' gestation or chorionic villus sampling (CVS) at about ten to 12 weeks' gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Requests for prenatal diagnosis of (typically) adult-onset diseases are not common. Differences in perspective may exist among medical professionals and within families regarding use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination. Although most centers would consider decisions about prenatal testing to be the choice of the parents, careful discussion of these issues is appropriate.
Preimplantation genetic diagnosis (PGD). Preimplantation genetic diagnosis may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see
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Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
| Gene Symbol | Chromosomal Locus | Protein Name | Locus Specific | HGMD |
|---|---|---|---|---|
| MAPT | 17q21.1 | Microtubule-associated protein tau | Alzheimer Disease & Frontotemporal Dementia Mutation Database alsod/MAPT genetic mutations |
MAPT |
Normal allelic variants: The gene consists of 15 exons. Several non-pathogenic polymorphisms that cause amino acid changes have been found.
Pathologic allelic variants: Pathogenic mutations consist of missense mutations and intronic and exonic mutations affecting alternative splicing of exon 10 [Hutton et al 1998, Heutink 2000]. (For more information, see Table A: locus-specific databases and HGMD above.)
Normal gene product: MAPT promotes tubulin polymerization, reduces microtubule instability, and plays a role in maintaining neuronal integrity, axonal transport, and axonal polarity. MAPT protein is abundant in both the central and peripheral nervous system. In brain, it is predominantly found in nerve cells where it is concentrated in nerve cell axons.
The tau protein isoforms found in human brain are encoded by eleven exons [Andreadis et al 1992]. A total of six different major MAPT mRNA transcripts are generated as a result of alternative splicing that encodes proteins of 352-441 amino acids [Goedert et al 1989]. In the carboxy-terminal part of MAPT, three or four tandem imperfect repeats are present containing domains important for the binding to microtubules. One alternatively spliced exon (exon 10) encodes the additional fourth repeat.
Alternative splicing of MAPT is developmentally regulated in that in immature brain only the transcript encoding the shortest isoform with three repeats is expressed, but in adult cerebal cortex all six isoforms are present. MAPT is post-translationally modified by phosphorylation in a dynamic process and it has been suggested that this is an additional mechanism to regulate MAPT function.
Abnormal gene product: Missense mutations lead to reduced binding capacity of the tau protein to microtubuli [Hasegawa et al 1998].
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals. GeneTests provides information about selected organizations and resources for the benefit of the reader; GeneTests is not responsible for information provided by other organizations.—ED.
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
6 June 2007 (cd) Revision: sequence analysis of the entire coding region available clinically
18 November 2005 (me) Comprehensive update posted to live Web site
5 August 2003 (me) Comprehensive update posted to live Web site
7 November 2000 (me) Review posted to live Web site
30 June 2000 (jvs) Original submission
