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TARDBP-Related Amyotrophic Lateral Sclerosis

, MD, , MD, PhD, and , MD, PhD.

Author Information
, MD
Department of Neurology, Neuromuscular Division
Washington University School of Medicine
St Louis, Missouri
, MD, PhD
Department of Neurology, Neuromuscular Division
Washington University School of Medicine
St. Louis, Missouri
, MD, PhD
Department of Neurology, Neuromuscular Division
Washington University School of Medicine
St. Louis, Missouri

Initial Posting: ; Last Revision: May 28, 2009.

Summary

Disease characteristics. TARDBP-related amyotrophic lateral sclerosis (TARDBP-related ALS) is characterized by upper motor neuron (UMN) and lower motor neuron (LMN) disease that appears indistinguishable from ALS of other known and unknown causes based on gender ratio, age of onset, symptom distribution, and severity of disease. The male to female ratio is 1.6 to 1. Mean age of onset is 54 ± 12 years. UMN manifestations can include stiffness, spasticity, hyperreflexia, and pseudobulbar affect; LMN manifestations often include weakness accompanied by muscle atrophy, fasciculations, and cramping. Limb-onset occurs in 80% and bulbar-onset in 20%. Affected individuals typically succumb to respiratory failure when phrenic and thoracic motor neurons become severely involved.

Diagnosis/testing. The diagnosis of ALS is established by clinical examination, neurophysiologic testing, and neuroimaging. TARDBP is the only gene associated with TARDBP-related ALS.

Management. Treatment of manifestations: Spasticity can be treated with a spasmolytic such as baclofen or a benzodiazepine; pseudobulbar affect can be treated with a tricyclic antidepressant or combination of quinidine and dextromethorphan; sialorrhea is often managed with anticholinergic medications (tricyclic antidepressants, scopolamine, atropine drops) or botulinum toxin injection of the salivary glands; antidepressants are often required to treat concurrent depression; it is reasonable to consider use of riluzole, the only FDA-approved treatment for any type of ALS.

Prevention of secondary complications: Percutaneous gastrostomy can be used to maintain adequate caloric intake in persons with significant bulbar involvement; appropriate bracing and stretching can minimize contractures; noninvasive ventilation can be initiated when appropriate.

Surveillance: At clinic visits: monitoring of ventilatory function and screening for depression.

Genetic counseling. TARDBP-related ALS is inherited in an autosomal dominant manner. The proportion of cases caused by de novo mutations is unknown. Each child of an individual with TARDBP-related ALS has a 50% chance of inheriting the mutation. Prenatal diagnosis for TARDBP-related ALS is possible if the disease-causing mutation has been identified in the family.

Diagnosis

Clinical Diagnosis

A diagnosis of TARDBP-related amyotrophic lateral sclerosis (TARDBP-related ALS) is established when a pathogenic TARDBP mutation is identified in an individual meeting clinical diagnostic criteria for ALS (i.e., characteristic signs and symptoms of progressive degeneration of upper motor neurons (UMNs) and lower motor neurons [LMNs]).

  • UMN manifestations include stiffness, spasticity, hyperreflexia, and pseudobulbar affect
  • LMN manifestations include weakness accompanied by muscle atrophy, fasciculations, and cramping

(See the El Escorial criteria [Brooks et al 2000])

Note: TARDBP-related ALS is clinically indistinguishable from ALS due to other causes.

For a more detailed description of these features, please refer to the Amyotrophic Lateral Sclerosis Overview.

Testing

Clinical testing in TARDBP-related ALS is identical to that for other forms of ALS, employing multiple modalities to exclude alternative diagnoses and to provide support for the diagnosis of ALS. Following a diagnosis of ALS, genetic testing for TARDBP mutations can be considered (see Testing Strategy).

Electromyography and nerve conduction studies (EMG/NCS). EMG/NCS are often used to support a diagnosis of ALS and to exclude mimics of ALS (e.g., polyradiculopathy, mononeuritis multiplex, multifocal motor neuropathy, sensory motor neuropathies). EMG/NCS in TARDBP-related ALS, as in other causes of ALS, demonstrates widespread denervation due to LMN loss in the setting of relatively preserved sensory responses [Gitcho et al 2008, Kühnlein et al 2008].

Neuroimaging. MRI of the brain and spinal cord are used in the evaluation to exclude alternate explanations for the observed symptoms, including polyradiculopathy and spinal cord or brain lesions. Although several imaging abnormalities have been directly attributed to ALS, including abnormal T2 signal along the corticospinal tracts and atrophy of the precentral gyrus, the poor sensitivity and specificity of these findings limit their usefulness in confirming the diagnosis of ALS [Grosskreutz et al 2008]. Although the imaging characteristics of TARDBP-related ALS have not been systematically investigated, single cases have had unremarkable MRI of the brain and cervical spinal cord [Kühnlein et al 2008, Pamphlett et al 2009].

Cerebrospinal fluid (CSF). Analysis of the CSF is primarily used to exclude mimics of ALS, including infectious polyradiculitis and carcinomatosis or lymphomatosis. TAR DNA-binding protein 43 (TDP-43), the protein encoded by TARDBP, has been detected in the CSF of individuals with ALS [Steinacker et al 2008, Kasai et al 2009], but has not yet been examined in persons with TARDBP-related ALS.

Neuropathology. Pathologic evaluation of the brain and spinal cord can be utilized to confirm a diagnosis of ALS post-mortem. One of the pathologic hallmarks of ALS is the presence of ubiquitin-immunoreactive cytoplasmic inclusions in degenerating cortical and spinal cord neurons. In non-SOD1 ALS, these cytoplasmic inclusions typically contain TDP-43, which is also reduced or absent from the nuclei of inclusion-containing cells [Neumann et al 2006, Davidson et al 2007]. TDP-43-positive inclusions have also been described in other neurodegenerative diseases [Freeman et al 2008, Uryu et al 2008, Arai et al 2009] and in several diseases of muscle [Weihl et al 2008, Küsters et al 2009, Olivé et al 2009].

The post-mortem pathology of five individuals with TARDBP-related ALS has been reported.

Molecular Genetic Testing

Gene. TARDBP is the only gene in which mutation causes TARDBP-related ALS.

Clinical testing

Sequence analysis. Mutation detection rate for sequence analysis should approach 100%, but will only identify single nucleotide substitutions or small insertions/deletions within exons or near exon/intron junctions.

No large deletions or insertions have been reported, but screening for these types of mutations have been limited to copy number analysis in 279 ALS patients [Guerreiro et al 2008] and to multiplexed amplicon quantification (MAQ) in another 237 ALS cases [Gijselinck et al 2009]. These findings should be considered preliminary until larger cohorts have been screened.

Table 1. Summary of Molecular Genetic Testing Used in TARDBP-Related Amyotrophic Lateral Sclerosis

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
TARDBPSequence analysisNucleotide substitutions, small insertions and deletions 4Approaches 100% 5

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. For issues to consider in interpretation of sequence analysis results, click here.

5. Because TARDBP-related ALS is defined by the presence of a mutation in TARDBP, and because mutation types that are not detected by sequence analysis (e.g., exonic or whole-gene deletions) have not been reported, the mutation detection rate for TARDBP using sequence analysis approaches 100%.

Testing Strategy

To establish the diagnosis in a proband

  • Establish a clinical diagnosis of ALS using clinical examination, neurophysiologic testing, and neuroimaging. Note: TARDBP-related ALS is clinically indistinguishable from ALS due to other causes.
  • Obtain a three-generation family history. The presence of ALS in a closely related family member (usually a parent) increases the probability that a TARDBP mutation may be found. If the proband is the only occurrence of ALS in their family, i.e. a simplex case, the likelihood of identifying a TARDBP mutation is lower. Note: To date, all reported pedigrees with TARDBP-related ALS show autosomal dominant inheritance.

Familial ALS (FALS) (i.e., presence of at least two affected family members)

Simplex/sporadic ALS (SALS) (i.e., single occurrence in a family). Sequencing of TARDBP in SALS can be performed, but the lower mutation prevalence (1.1%) in this population should be taken into consideration.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

More than 80 persons with TARDBP-related ALS have been described in the literature. The spectrum of clinical disease in these individuals appears to overlap significantly with idiopathic and SOD1-related ALS, including gender ratio, age of onset, symptom distribution, and severity of disease.

The male to female ratio is 1.6 to 1.

Mean age of onset is 54 ± 12 years (mean ± SD). The range of onset is age 20 to 83 years. This is similar to the age of onset in SALS and non-SOD1-related FALS.

Most patients with TARDBP-related ALS meet El Escorial criteria for ALS [Brooks et al 2000] and have both UMN and LMN involvement. Although LMN involvement is predominantly common [Gitcho et al 2008, Kabashi et al 2008, Kühnlein et al 2008, Corrado et al 2009], no individuals with pure UMN involvement (primary lateral sclerosis) have been reported.

Limb-onset is noted in 80% of TARDBP-related ALS and bulbar-onset in 20%. Intra- and interfamilial variability in the site of onset is observed even with the same mutation (see Genotype-Phenotype Correlations).

Although ALS and FTLD frequently share TDP-43 aggregates on pathology, no TARDBP mutations have yet been identified in patients with pure FTLD. However, several patients with FTLD and FTLD-MND were recently found to have the p.Gly295Ser mutation [Benajiba et al 2009] (see Genetically Related Disorders). Other neurocognitive symptoms reported amongst TARDBP-ALS patients include Alzheimer-type dementia [Corrado et al 2009], anxiety, apathy, and agitation [Kabashi et al 2008].

As with other forms of ALS, individuals with TARDBP-related ALS die of respiratory failure when phrenic and thoracic motor neurons become severely involved.

The mean disease duration prior to death is 50 ± 36 months (mean ± SD) but ranges from one to 13 years and may vary by mutation (see Genotype-Phenotype Correlations).

Genotype-Phenotype Correlations

Reliable correlations between specific mutations and clinical phenotype are difficult to make at present. However:

Penetrance

Penetrance is difficult to estimate at present for the following reasons:

  • Few unaffected individuals in families with TARDBP-related ALS have been genotyped or longitudinally followed for the emergence of symptoms.
  • The parents and relatives of simplex ALS cases with TARDBP mutations have not been reported in detail.

Importantly, the identification of 28 individuals with simplex ALS with TARDBP mutations argues that either de novo mutations are common and/or that these variants show incomplete penetrance.

Prevalence

Across published series, more than 3100 persons with ALS have been tested for TARDBP mutations, either by sequencing of the entire gene or by sequencing of exon 6 (where most mutations are located) [Rutherford et al 2008, Winton et al 2008, Del Bo et al 2009, Lemmens et al 2009].

The prevalence of TARDBP mutations in:

Pathogenic mutations in TARDBP occur worldwide, including:

A higher prevalence in Italian and French populations has been reported [Kabashi et al 2008, Corrado et al 2009, Daoud et al 2009, Del Bo et al 2009].

Differential Diagnosis

For a detailed discussion of these disorders and the differential diagnosis of ALS, see Amyotrophic Lateral Sclerosis Overview.

TARDBP-associated ALS must be differentiated from mimics of ALS. Detailed clinical evaluation (as outlined above) usually allows the exclusion of other disorders. The rate of misdiagnosis in ALS is highest in individuals presenting with purely LMN findings [Traynor et al 2000].

The mimics of ALS from any cause are numerous and include:

Other genes associated with FALS* include:

  • ALS1. SOD1 (encoding the protein superoxide dismutase)
  • ALS4. SETX (encoding the protein senataxin)
  • ALS6. FUS/TLS (encoding the protein fused in sarcoma/translated in liposarcoma)
  • ALS8. VAPB (encoding the protein vesicle-associated membrane protein-associated protein B/C)
  • ALS9. ANG (encoding the protein angiogenin)
  • DCTN1 (encoding the protein dynactin)

* Mutations in many of these genes have also been identified in small numbers of simplex cases of ALS (i.e., a single occurrence in a family).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with TARDBP-related ALS (or any other form of ALS), the following evaluations are recommended:

  • EMG/NCS to document the regions of involvement
  • Pulmonary function testing to detect and stage respiratory involvement
  • Speech and swallowing evaluation if dysarthria and/or dysphagia are present, to direct care to minimize risk of aspiration and to initiate augmentative communication strategies for possible loss of verbal communication
  • Physical and occupational therapy evaluation to determine what adaptive devices are needed to maximize function
  • Nutritional evaluation
  • Screening for depression and need for psychosocial support

Treatment of Manifestations

The management of TARDBP-related ALS is identical to that of ALS due to other causes, and is outlined in the American Academy of Neurology practice parameter on this topic [Miller et al 1999].

  • Spasticity can be treated with a spasmolytic such as baclofen or a benzodiazepine.
  • Pseudobulbar affect can be treated with a tricyclic antidepressant or combination of quinidine and dextromethorphan.
  • Sialorrhea is often managed with anticholinergic medications (tricyclic antidepressants, scopolamine, atropine drops) or botulinum toxin injection of the salivary glands.
  • Antidepressants are often required to treat concurrent depression.
  • Riluzole is the only FDA-approved treatment for any type of ALS. Although there are no efficacy data specifically for TARDBP-related ALS, strong consideration should be given to its use [Miller et al 2007].

Prevention of Secondary Complications

Adequate nutrition and weight maintenance are essential. Percutaneous gastrostomy is often appropriate to maintain adequate caloric intake in persons with significant bulbar involvement.

Joint contractures can occur, are often painful, and can interfere with care-giving. Appropriate bracing and stretching can minimize contractures.

Early initiation of noninvasive ventilation has been shown to prolong survival [Farrero et al 2005].

Surveillance

Monitoring of the forced vital capacity and other parameters of ventilation should be performed at clinic visits to determine the appropriate time to offer noninvasive ventilation.

Routine screening for depression at clinic visits is appropriate.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Although no current clinical trials are specifically designed to target TARDBP-related ALS, many are addressed in the broader category of ALS.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

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. —ED.

Mode of Inheritance

TARDBP-related amyotrophic lateral sclerosis is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Many individuals diagnosed with TARDBP-related ALS have an affected parent.
  • A proband with TARDBP-related ALS may have the disorder as the result of a new gene mutation. The frequency of de novo mutations is unknown because relatives of simplex cases have not been sufficiently evaluated to exclude low penetrance.
  • If the disease-causing mutation found in the proband cannot be detected in the DNA of either parent (assuming exclusion of non-paternity), two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband. Although no instances of germline mosaicism have been reported, it remains a possibility.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include thorough neurologic evaluation and molecular genetic testing for the TARDBP mutation identified in the proband. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of failure by health care professionals to recognize the syndrome and/or a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluation of relatives has been performed.

Note: (1) Although most individuals diagnosed with TARDBP-related ALS 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, or late onset or reduced penetrance of the disease in the affected parent. (2) If the parent is the individual in whom the mutation first occurred s/he may have somatic mosaicism for the mutation and may be mildly/minimally affected.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband’s parents.
  • If a parent of the proband is affected, the risk to the sibs of inheriting the TARDBP mutation is 50%.
  • The sibs of a proband with clinically unaffected parents are still at increased risk (for the disorder) because of the possibility of reduced penetrance in a parent.
  • If the disease-causing mutation found in the proband cannot be detected in the DNA of either parent, the risk to sibs is low, but greater than that of the general population, because of the possibility of germline mosaicism.

Offspring of a proband. Each child of an individual with TARDBP-related ALS has a 50% chance of inheriting the mutation.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected or has a TARDBP mutation, his or her family members may be at risk.

Related Genetic Counseling Issues

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 maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Testing of at-risk asymptomatic adults. Presymptomatic testing for a TARDBP mutation is complicated because the penetrance is unknown, the age of onset is not predictable, and preventive measures do not exist. Because of the individualized nature of predictive testing, consultation with a genetic counselor and a psychologist to obtain informed consent is recommended. At this time, no established testing protocol (as in, e.g., Huntington disease) exists, although establishment of such protocols has been suggested. However, to err on the side of caution, testing centers often follow a similar protocol.

Testing of at-risk individuals during childhood. Consensus holds that asymptomatic individuals younger than 18 years of age who are at risk for adult-onset disorders should not have testing. The principal reasons against testing such individuals are that it removes their choice to know or not know this informaiton, it raises the possibility of stigmatization within the family and in other social settings, and it could have serious educational and career implications. In addition, no preventive treatment is available for this disorder. See also the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset disorders 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.

Individuals younger than age 18 years who are symptomatic usually benefit from having a specific diagnosis established.

Family planning

  • The optimal time for determination of genetic risk is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

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.

Prenatal Testing

If the disease-causing mutation has been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

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 testing for adult-onset conditions (like TARDBP-related ALS) are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although decisions about prenatal testing are the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Amyotrophic Lateral Sclerosis Association (ALS Association)
    27001 Agoura Road
    Suite 250
    Calabasas Hills CA 91301-5104
    Phone: 800-782-4747 (Toll-free Patient Services); 818-880-9007
    Fax: 818-880-9006
    Email: alsinfo@alsa-national.org
  • Amyotrophic Lateral Sclerosis Society of Canada
    3000 Steeles Avenue East
    Suite 200
    Markham Ontario L3R 4T9
    Canada
    Phone: 800-267-4257 (toll-free); 905-248-2052
    Fax: 905-248-2019
  • Les Turner ALS Foundation (Amyotrophic Lateral Sclerosis)
    5550 West Touhy Avenue
    Suite 302
    Skokie IL 60077-3254
    Phone: 888-257-1107 (toll-free); 847-679-3311
    Fax: 847-679-9109
    Email: info@lesturnerals.org
  • Muscular Dystrophy Association - USA (MDA-ALS Division)
    3300 East Sunrise Drive
    Tucson AZ 85718
    Phone: 800-344-4863 (toll-free); 800-572-1717 (toll-free)
    Email: mda@mdausa.org
  • National Library of Medicine Genetics Home Reference
  • NCBI Genes and Disease

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. TARDBP-Related Amyotrophic Lateral Sclerosis: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for TARDBP-Related Amyotrophic Lateral Sclerosis (View All in OMIM)

605078TAR DNA-BINDING PROTEIN; TARDBP
612069AMYOTROPHIC LATERAL SCLEROSIS 10, WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA; ALS10

Normal allelic variants. TARDBP has six exons, five of which are coding.

A p.Asp65Glu substitution was identified in one normal individual of African descent and is a presumed normal variant [Guerreiro et al 2008].

The p.Ala90Val variant was found in one individual with FTLD-MND [Winton et al 2008] and in multiple controls of northern European background [Guerreiro et al 2008, Kabashi et al 2008, Sreedharan et al 2008]. Despite being present in controls, experimental data suggests that this allele may produce abnormal cytoplasmic aggregation of the TDP-43 [Winton et al 2008]. Therefore, the p.Ala90Val substitution may be a normal variant, or alternatively may convey susceptibility to developing FTD/ALS.

Pathogenic allelic variants. More than 30 potentially pathogenic TARDBP variants have been identified in familial (FALS) and/or simplex cases of ALS (SALS) (see Table 2). Although four of these variants have been found in more than one family, and three are present in both FALS and SALS cases, more than 50% of these potentially pathogenic variants have been identified in a single individual with SALS. This may suggest a high percentage of private (i.e., unique) mutations in TARDBP-related ALS [Corrado et al 2009]. In contrast, the p.Ala382Thr pathogenic variant has been frequently detected in French and Italian ALS patients on a shared haplotype, indicating a shared ancestral founder [Kabashi et al 2008, Corrado et al 2009, Del Bo et al 2009].

All pathogenic variants appear to affect highly conserved amino acids, and 93% of known mutations reside in exon 6. The two non-exon 6 variants are p.Asp169Gly (in exon 4) [Kabashi et al 2008] and the 3’ UTR variant c.1462 T>C [Daoud et al 2009]. Each has been found in only one individual with SALS. Only one nonsense mutation has been described to date (a single base-pair insertion producing frameshift and a premature stop codon p.Tyr374Ter [Daoud et al 2009]), with the rest being missense mutations.

Table 2. Selected TARDBP Allelic Variants

Class of
Variant Allele
DNA Nucleotide Change
(Alias 1)
Protein Amino
Acid Change
Reference
Sequences
Normal c.269C>Tp.Ala90Val 2NM_007375​.3
NP_031401​.1
c.195T>A or c.195T>G 3p.Asp65Glu
Pathogenicc.506A>Gp.Asp169Gly
c.800A>Gp.Asn267Ser
c.859G>Ap.Gly287Ser
c.869G>Cp.Gly290Ala
c.881G>Cp.Gly294Ala
c.881G>Tp.Gly294Val 4
c.883G>Ap.Gly295Ser 4
c.883G>Cp.Gly295Arg
c.892G>Ap.Gly298Ser
c.931A>Gp.Met311Val
c.943G>Ap.Ala315Thr 5
c.991C>Ap.Gln331Lys
c.995G>Ap.Ser332Asn
c.1004G>Ap.Gly335Asp
c.1009A>Gp.Met337Val 5
c.1028A>Gp.Gln343Arg
c.1035C>A p.Asn345Lys
c.1042G>Tp.Gly348Cys 5
c.1055A>Gp.Asn352Ser
c.1083G>Tp.Arg361Ser
c.1097C>Gp.Pro363Ala
c.1121_1122dupAp.Tyr374Ter
c.1135T>Cp.Ser379Pro
c.1136C>Gp.Ser379Cys
c.1144G>Cp.Ala382Pro
c.1144G>Ap.Ala382Thr 4, 5
c.1147A>Gp.Ile383Val
c.1168A>Gp.Asn390Asp
c.1169A>Gp.Asn390Ser
c.1178C>Tp.Ser393Leu
c.*83T>C 6
(1462T>C)
--

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

2. May be a variant that is normal or confers susceptibility to FTD/ALS. See Normal allelic variants.

3. The precise nucleotide change is not known.

4. Identified in both FALS and SALS

5. Identified in affected individuals in more than one family

6. * indicates location in 3’UTR, number of nucleotides beyond stop codon

Normal gene product. TDP-43 comprises 414 amino acids encoded by TARDBP exons 2-6. TDP-43 is a ubiquitously expressed nuclear protein with structural similarities to the hnRNP A/B family of RNA binding proteins and is known to regulate DNA transcription, alternative splicing, and mRNA stability [Buratti & Baralle 2008]. Although information regarding the role of TDP-43 in normal cellular function is limited, it has been shown to influence cell cycle progression by modulating CDK6 mRNA levels in dividing cells [Ayala et al 2008].

Abnormal gene product. All but one of the clearly pathogenic variants thus far identified are located in exon 6. These cluster in the C-terminal glycine-rich domain of the TDP-43, an area that interacts with other hnRNPs to regulate alternative splicing [Buratti et al 2005]. Mutations in TARDBP may promote TDP-43 aggregation in cortical and spinal motor neurons. In TARDBP-related ALS, TDP-43 positive aggregates are made up of phosphorylated, ubiquitinated C-terminal fragments of the protein, and are typically cytosolic. Furthermore, a decrease in normal nuclear TDP-43 staining is often seen in these cells [Neumann et al 2006, Davidson et al 2007]. How the disease-associated mutations in TARDBP influence TDP-43 function, proteolysis, and aggregation is unknown.

Notably, TDP-43 inclusions are not present in humans with SOD1-related ALS or in mouse models that overexpress disease mutant SOD1, suggesting that SOD1-related ALS may have a different underlying pathophysiology than TARDBP-related ALS [Mackenzie et al 2007, Robertson et al 2007]. Furthermore, TDP-43 positive inclusions are not specific to ALS, and are found in other neurodegenerative diseases [Freeman et al 2008, Uryu et al 2008, Arai et al 2009] as well as several diseases of muscle [Weihl et al 2008, Küsters et al 2009, Olivé et al 2009].

References

Literature Cited

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Chapter Notes

Revision History

  • 28 May 2009 (cd) Revision: prenatal testing available
  • 23 April 2009 (et) Review posted live
  • 14 November 2008 (rhb) Original submission
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