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TARDBP-Related Amyotrophic Lateral Sclerosis

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

Author Information

Initial Posting: ; Last Update: March 12, 2015.

Summary

Clinical 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.

Agents/circumstances to avoid: Long-term use of minocycline; excessive exercise to the point of inducing fatigue.

Genetic counseling.

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

Diagnosis

A diagnosis of TARDBP-related amyotrophic lateral sclerosis (TARDBP-related ALS) is established when a TARDBP pathogenic variant 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.

See Amyotrophic Lateral Sclerosis Overview for a more detailed description of these features.

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 pathogenic variants 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]. If frontotemporal dementia is also present, atrophy of the frontal and temporal lobes may be present [Floris et al 2015]. 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 conditions with overlapping features 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 of unknown cause [Steinacker et al 2008, Kasai et al 2009]. It has only been examined in a single individual with TARDBP-related ALS, and this individual had substantially higher levels than individuals with sporadic ALS [Nozaki et al 2010].

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 (including TARBP-associated 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]. However, TDP-43-positive inclusions are not specific for ALS and 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].

Molecular Genetic Testing

Gene. TARDBP is the only gene in which pathogenic variants are known to cause TARDBP-related ALS.

Clinical testing

Table 1.

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

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method
TARDBPSequence analysis 2Approaches 100% 3
Deletion/duplication analysis 4See footnote 5
1.

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene.

2.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

3.

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

4.

Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

5.

No large deletions or insertions have been reported. Screening for these types of variants has been reported in 714 patients using rt-PCR or multiplexed amplicon quantification (MAQ) [Guerreiro et al 2008, Rutherford et al 2008, Bäumer et al 2009, Benajiba et al 2009, Gijselinck et al 2009]. Since the proposed mechanism that leads to TARDBP-related ALS is gain-of-function of TARDBP, it is unlikely that copy number variants in TARDBP will comprise a significant number of cases.

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 resulting from 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 pathogenic variant 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 pathogenic variant is lower.
    Note: (1) To date, all reported pedigrees with TARDBP-related ALS show autosomal dominant inheritance; (2) Several genetic causes of ALS are more common than TARDBP-related ALS (see below).

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

Single-gene testing. One genetic testing strategy is serial single-gene molecular genetic testing based on the order in which pathogenic variants most commonly occur.

  • In most white populations, molecular genetic testing in the following order is recommended:
    • Testing for an expansion of the hexanucleotide repeat in C9ORF72 (accounting for ~40%-50% of FALS) should be done first.
    • If no expansion is identified in C9ORF72, molecular genetic testing of SOD1 (accounting for ~20% of FALS) should be considered next.
    • If molecular genetic testing of C9ORF72 and SOD1 does not reveal a pathogenic variant, molecular genetic testing of TARDBP and/or FUS (together accounting for <5% of cases) should be considered next.
  • In individuals of Asian or African background, molecular genetic testing of SOD1 should be considered first.
  • In Sardinia, where C9ORF72 expansions and TARDBP pathogenic variants account for most cases and at times coexist in the same family, simultaneous molecular genetic testing of both genes could be considered.

Multi-gene panel. An alternative genetic testing strategy is use of a multi-gene panel that includes C9ORF72, SOD1, TARDBP, and other genes of interest (see Differential Diagnosis). Note: The genes included and the methods used in multi-gene panels vary by laboratory and over time.

More comprehensive genomic testing. (when available) including exome sequencing, genome sequencing and mitochondrial sequencing may be considered if single-gene testing (and/or use of a multi-gene panel) fails to confirm a diagnosis in an individual with features of ALS. For more information on comprehensive genome sequencing click here.

Other. In some cases testing for other rare genetic causes of FALS can be considered, although these typically have a distinctive clinical presentation or autosomal recessive inheritance pattern (see Amyotrophic Lateral Sclerosis Overview).

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.

Clinical Characteristics

Clinical Description

More than 200 individuals with TARDBP-related ALS have been described in the literature. The spectrum of clinical disease has been defined by a recent analysis of all published reports of individuals with a TARDBP pathogenic variant, noting substantial differences between Asian and non-Asian individuals [Corcia et al 2012].

The average age of symptom onset is 53.5 ± 12.3 years (mean ± SD), which is similar to affected individuals with SOD1 pathogenic variants but substantially earlier than those with simplex ALS and familial ALS without an identified pathogenic variant.

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

More than half of non-Asian individuals with a TARDBP pathogenic variant have first symptoms in the upper extremities, a rate that is double that found in other forms of the disease. However, bulbar onset appears to predominate in Asian individuals [Corcia et al 2012] and intra- and interfamilial variability in the site of onset is observed even with the same pathogenic variant (see Genotype-Phenotype Correlations).

As with other forms of ALS, individuals with TARDBP-related ALS die of respiratory failure when phrenic and thoracic motor neurons become severely involved. However, the median disease survival in non-Asian individuals with a TARDBP pathogenic variant is 62 months, which is significantly longer than the survival of individuals without a known TARDBP pathogenic variant, either with simplex ALS (35 months) or familial ALS (31 months). Interestingly, Asian individuals with a TARDBP pathogenic variant appear to have even slower rates of progression of disease, with median disease duration of 108 months [Corcia et al 2012]. Disease duration is also influenced by which pathogenic variant is present, and although the median survival is favorable, progression to death within a year is not uncommon (see Genotype-Phenotype Correlations).

Although these trends are visible in aggregated cohorts of affected individuals, the range of age at onset, pattern of symptoms at onset, and disease duration are quite broad and substantially overlap with all other causes of ALS. As a result, phenotypic features do little to inform whether genetic testing should be pursued.

Genotype-Phenotype Correlations

Correlations between specific pathogenic variants and clinical phenotype are available for only the most commonly reported pathogenic variants in TARDBP. For the vast majority of pathogenic variants, the numbers are too few to draw reliable conclusions. However:

Penetrance

Like pathogenic variants in other ALS-related genes (e.g., SOD1), penetrance is clearly incomplete. This is evident from the number of individuals with apparently simplex ALS who have a TARDBP pathogenic variant, which may have been inherited from an ostensibly asymptomatic (or undiagnosed) parent. However, accurate estimates are difficult to achieve 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 apparently simplex ALS cases with TARDBP pathogenic variants have not been reported in detail.

Prevalence

The prevalence of TARDBP pathogenic variants in:

Pathogenic variants in TARDBP have been reported worldwide:

A higher prevalence in Italian, French, and Taiwanese populations has been reported [Kabashi et al 2008, Corrado et al 2009, Daoud et al 2009, Del Bo et al 2009]. The p.Ala382Thr pathogenic variant is very common in Sardinia due to a founder effect. It accounts for 80% of familial ALS and 9% of simplex cases [Orrù et al 2012].

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 conditions that have overlapping features of ALS. Detailed clinical evaluation (as outlined above) is usually sufficient to exclude 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:

The number of other genes associated with FALS (see note) has been rapidly increasing and is tracked at the ALSoD site. Some examples include:

  • ALS1. SOD1 (encoding the protein superoxide dismutase)
  • ALS4. SETX (encoding the protein probable helicase senataxin)
  • ALS6. FUS/TLS (encoding the protein )
  • ALS8. VAPB (encoding the protein vesicle-associated membrane protein-associated protein B/C)
  • ALS9. ANG (encoding the protein angiogenin)
  • DCTN1 (encoding the protein dynactin subunit 1)

Note: Pathogenic variants 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 and needs 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
  • Clinical genetics consultation

Treatment of Manifestations

The management of TARDBP-related ALS is identical to that of ALS resulting from other causes, and is outlined in the American Academy of Neurology practice parameter on this topic [Miller et al 2009a, Miller et al 2009b].

  • 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].

Note: See Author Notes, Miller Laboratory for a link to investigative reports on accurate assessments of the risks and benefits of specific proposed therapies.

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.

Agents/Circumstances to Avoid

Long-term use of minocycline, which was studied in a randomized-controlled trial in individuals with ALS, was associated with worse outcomes [Gordon et al 2007].

Excessive exercise to the point of inducing fatigue in already weakened muscles is cautioned against by many practitioners based on experience.

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 ongoing trials address 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 usually inherited in an autosomal dominant manner. In very rare instances, an affected individual may have biallelic pathogenic variants in TARDBP [Borghero et al 2011] or may have digenic pathogenic variants (i.e., a pathogenic variant in TARDBP with a coexisting repeat expansion in C9ORF72 [van Blitterswijk et al 2012]).

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 de novo pathogenic variant. The frequency of TARDBP de novo pathogenic variants is unknown because relatives of simplex cases have not been sufficiently evaluated to exclude low penetrance.
  • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, two possible explanations are germline mosaicism in a parent or 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 pathogenic variant include thorough neurologic evaluation and molecular genetic testing for the TARDBP pathogenic variant 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 evaluations have been performed on the parents of the proband.

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 pathogenic variant first occurred s/he may have somatic mosaicism for the pathogenic variant 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 pathogenic variant 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 pathogenic variant found in the proband cannot be detected in the leukocyte 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 pathogenic variant.

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 pathogenic variant, his or her family members may be at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant or clinical evidence of the disorder, it is likely that the pathogenic variant occurred de novo in the proband. 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 pathogenic variant 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 (e.g., as in 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 age 18 years who are at risk for adult-onset disorders should not have molecular genetic testing. The principal reasons against testing such individuals are that testing 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. In addition, no preventive treatment is available for ALS. See also the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Academy of Pediatrics and American College of Medical Genetics and Genomics policy statement: ethical and policy issues in genetic testing and screening of children.

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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the TARDBP pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for TARDBP-related ALS are possible.

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.

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)
    222 S. Riverside Plaza
    Suite 1500
    Chicago IL 60606
    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

Locus NameGeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
ALS10TARDBP1p36​.22TAR DNA-binding protein 43ALS mutation database (TARDBP)
TARDBP database
TARDBPTARDBP

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) 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

Gene structure. TARDBP has six exons, five of which are coding. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. More than 35 TARDBP coding variants have been identified in familial (FALS) and/or simplex cases of ALS (SALS). The majority of these variants have been identified in single simplex cases or in probands of families for which segregation data are unavailable. The argument for the pathogenicity of these variants has historically stood on their location (within exon 6 near clearly causative pathogenic variants) and their absence in control subjects (usually a modest number). This fact could suggest a high percentage of private (i.e., unique) variants in TARDBP-related ALS [Corrado et al 2009].

However, exome and genome sequencing in large non-ALS populations, such as the 1000 Genomes Project or ExAC browser, have identified infrequent and rare coding variants across TARDBP, including some within exon 6. In fact, six variants previously identified in patients with ALS are now found in these databases (but always in <1 in 30,000 individuals). Determining the significance of this group of variants is difficult in the absence of additional genetic data (e.g., additional cases or segregation within a family). A clear classification as pathogenic or benign may not be possible until functional assays are developed that reliably distinguish between these groups.

Evidence for pathogenicity is much clearer for a minority of published variants (Table 2). Some have been found in more than one family or simplex case (p.Asn267Ser; p.Gly287Ser; p.Ala315Thr; p.Met337Val; p.Asn352Ser) or have been found in both FALS and SALS cases (p.Gly294Val; p.Gly295Ser; p.Gly348Cys; p.Ala382Thr). All clearly pathogenic variants affect highly conserved amino acids and reside in exon 6. This finding may be biased because exon 6 has often been selectively resequenced.

Two non-exon 6 variants are p.Asp169Gly (in exon 4) [Kabashi et al 2008] and the 3’ UTR variant 1462T>C [Daoud et al 2009]. However, each has been found in only one individual with SALS, making it unclear if these are truly pathogenic. Only one pathogenic nonsense variant has been described to date (a single base-pair duplication-producing frameshift and a premature stop codon p.Tyr374Ter [Daoud et al 2009]).

Benign variants. Given the complexities of distinguishing benign from pathogenic rare variants, the interpretation of the p.Ala90Val variant has been particularly challenging. The p.Ala90Val variant was originally found in an individual with FTLD-MND [Winton et al 2008], but has subsequently been seen in other patient cohorts. However, it is also consistently found in controls of northern European background as well [Guerreiro et al 2008, Kabashi et al 2008, Sreedharan et al 2008]. By genetic evidence alone, it is therefore likely to be benign. However, experimental data suggest that this allele causes abnormal cytoplasmic aggregation of TDP-43 [Winton et al 2008], and therefore it remains possible that the p.Ala90Val substitution may convey susceptibility to developing FTD/ALS.

Table 2.

TARDBP Variants Discussed in This GeneReview

Variant ClassificationDNA Nucleotide Change
(Alias 1)
Predicted Protein ChangeReference Sequences
Uncertain Significancec.269C>Tp.Ala90Val 2, 3NM_007375​.3
NP_031401​.1
c.506A>Gp.Asp169Gly
c.1121dupp.Tyr374Ter
c.*83T>C 4
(1462T>C)
(3’ untranslated region)
Pathogenicc.800A>Gp.Asn267Ser 3, 5
c.859G>Ap.Gly287Ser 3, 5
c.881G>Tp.Gly294Val 3, 6, 7
c.883G>Ap.Gly295Ser 6, 7
c.892G>Ap.Gly298Ser 5, 7
c.943G>Ap.Ala315Thr 5, 8
c.1009A>Gp.Met337Val 5, 8
c.1042G>Tp.Gly348Cys 5, 6
c.1055A>Gp.Asn352Ser 5
c.1144G>Ap.Ala382Thr 5, 6, 9

Note on variant classification: Variants listed in the table have been provided by the authors. 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 (varnomen​.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 may confer susceptibility to FTD/ALS

3.

Variant is also rarely found in population controls.

4.

* indicates location in 3’UTR and number of nucleotides beyond the normal stop codon.

5.

Identified in affected individuals in more than one family

6.

Identified in both FALS and SALS

7.

Limited evidence of segregation

8.

Convincing evidence of segregation

9.

Familial and simplex cases share founder haplotype.

See Table 3 (pdf) for a more complete list of TARDBP variants of uncertain clinical significance.

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, both loss of function and overexpression are deleterious in a wide variety of cellular contexts in vitro and in vivo [Baloh 2011].

Abnormal gene product. Most 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] but is also critically involved in TDP-43 self-aggregation and has properties similar to prion-related domains in yeast [Cushman et al 2010, Udan & Baloh 2011]. In TARDBP-related ALS, TDP-43 positive aggregates are phosphorylated and ubiquitinated, and are present in both the cytoplasm and the nucleus. Because a decrease in normal nuclear TDP-43 staining is often seen in these cells, loss of function has also been proposed to play a role in disease [Neumann et al 2006, Davidson et al 2007]. While pathogenic variants in TARDBP have been shown to influence TDP-43 proteolysis and aggregation, the exact role they play in promoting ALS remains poorly understood [Baloh 2012].

Importantly, TDP-43 positive inclusions are not specific to ALS, and are found in numerous 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].

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Chapter Notes

Revision History

  • 12 March 2015 (me) Comprehensive update posted live
  • 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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