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No Pathogenic GNAL Mutations in 192 Sporadic and Familial Cases of Cervical Dystonia

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Gavin Charlesworth
Gavin Charlesworth
Gavin Charlesworth
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Kailash Bhatia at University College London
Kailash Bhatia
Nicholas Wood at University College London
Nicholas Wood
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References
1. Heinzen EL, Swoboda KJ, Hitomi Y, et al. De novo mutations in
ATP1A3 cause alternating hemiplegia of childhood. Nat Genet.
2012;44:1030-1034.
2. Rosewich H, Thiele H, Ohlenbusch A, et al. Heterozygous de-novo
mutations in ATP1A3 in patients with alternating hemiplegia of
childhood: a whole-exome sequencing gene-identification study.
Lancet Neurol. 2012;11:764-773.
3. Ishii A, Saito Y, Mitsui J, et al. Identification of ATP1A3
mutations by exome sequencing as the cause of alternating
hemipleg ia of c hild hood in Japanese patients. PLoS One. 20 13;
8:e56120.
4. Brash ear A, Dobyns WB, de Carvalho Aguiar P, et al. The
phenotypic spectrum of rapid-onset dystonia-parkinsonism
(RDP) and mutations in the ATP1A3 gene. Brain. 2 007;13 0:
828-835.
5. Ozelius LJ. Clinical spectrum of disease associated with ATP1A3
mutations. Lancet Neurol. 2012;9:741-743.
6. Zanotti-Fregonara P, Vidailhet M, Kas A, et al. [
123
I]-FP-CIT and
[
99m
Tc]-HMPAO single photon emission computed tomography in
a new sporadic case of rapid-onset dystonia-parkinsonism. J Neu-
rol Sci. 2008;273:148-151.
7. Anselm IA, Sweadner KJ, Gollamudi S, Ozelius LJ, Darras BT.
Rapid-onset dystonia-parkinsonism in a child with a novel
ATP1A3 gene mutation. Neurology. 2009;73:400-401.
8. Roubergue A, Roze E, Vuillaumier-Barrot S, et al. The multiple
faces of the ATP1A3-related dystonic movement disorder. Mov
Disord. 2013;28:1457-1459.
No Pathogenic GNAL Mutations
in 192 Sporadic and Familial
Cases of Cervical Dystonia
Recently, using a whole exome sequencing approach,
mutations in GNAL were identified as a novel cause of pri-
mary dystonia by one group
1
and subsequently confirmed by
another.
2
Mutations in this gene appear to cause autosomal
dominant, primary dystonia with a cervical predilection and
evidence of incomplete penetrance.
1
The initial discovery paper by Fuchs et al reported GNAL
mutations in 6 out of 39 families screened (15%). How-
ever, in the subsequent study by Vemula et al, only 3 GNAL
mutations were detected in 760 subjects with familial or
sporadic primary dystonia (<0.5%). An accurate estimate of
the prevalence of GNAL mutations is important as a muta-
tion frequency of 15% would justify early and widespread
genetic testing of GNAL in familial dystonia, whereas a fre-
quency of <0.5% would not.
We screened GNAL by Sanger sequencing using the DNA
samples from 192 probands (136 female and 56 male) with
either familial or sporadic cervical dystonia, selected from a
library of research samples on the basis of a clinical description
of focal or segmental dystonia that included the cervical region.
Local ethics committee approval was obtained for the study. A
family history, defined as one or more first or second-degree
relatives with dystonia, was recorded in 84 cases. Tremor was
recorded in 53 cases. All familial cases had been screened for
TOR1A, THAP1 and ANO3 mutations and were negative.
TABLE 1. Comparison of AHC, DYT12, and patients with the ATP1A3 p.D923N mutation
AHC Present case Case 2
7
Cases 3, 4, and 5
8
Case 6
8
DYT12
Onset age <18 mo 2 y 4 y 2 mo, 2 y, 3 y 8 mo 4 y<
Dystonia Episodic Episodic, long-lasting, 2 y Fixed, 4 y Episodic, 2 mo, 8 y Episodic, 8 mo Fixed
Hemiplegia Episodic Episodic, 2 y Flaccidity Episodic 2 y, 2 y, 3 y Episodic 2y No
Seizure Frequent No No No No No
Fluctuation Frequent Positive Positive Positive Positive No
Triggers Fever, stress Fever, stress Fever Exercise Fever, exercise Fever, stress
Muscle tone Hypotonia Mild hypotonia Hypotonia NA NA Normal
Motor delay Mild to severe Mild delay Mild delay NA NA No
Ataxia Frequent Positive Positive Positive NA Frequent
Dysarthria,
dysphagia
Frequent Positive Positive Positive NA Frequent
Cognitive
deficit
Frequent No Lost words Borderline to mild
mental deficiency
Mild mental
deficiency
No
Causative
gene
ATP1A3 (D923Y in 1 case) ATP1A3 (D923N) ATP1A3 (D923N) ATP1A3 (D923N) ATP1A3 (D923N) ATP1A3 (D923N in
case 1)
Familial Rare No No Positive Positive Positive
Case 2 is a patient from Anselm’s article.
7
Cases 3, 4, and 5 are patients II-2, III-2, and III-3 from Roubergue’s article.
8
Case 6 is patient IV-1 from Roubergue’s article.
8
AHC, alternating hemiplegia of childhood; DYT12, rapid-o nset dystonia–parkinsonism; NA, not available.
-------------------------------------------- ----------------
Study funding: Supported by a Bachman-Strauss Dystonia and
Parkinson Foundation grant.
Relevant conflicts of interest/financial disclosures: Gavin Charles-
worth reports no disclosures. Kailash P. Bhatia has received honoraria/
financial support to speak/attend meetings from GSK, Boehringer-
Ingelheim, Ipsen, Merz, and Orion pharma companies. He holds grants
from the Bachmann-Strauss Dystonia Parkinson foundation, the Dystonia
Society UK and the Halley Stewart Trust. Nicholas W. Wood holds grants
from the Bachmann-Strauss Dystonia Parkinson foundation, the MRC
and the Wellcome Trust.
Received: 1 July 2013; Revised: 11 August 2013;
Accepted: 19 August 2013
Published online 12 November 2013 in Wiley Online Library
(wileyonlinelibrary.com). DOI: 10.1002/mds.25713
LETTERS: NEW OBSERVATIONS
154 Movement Disorders, Vol. 29, No. 1, 2014
Primers were designed to amplify all exons, the exon/
intron boundaries and the 5
0
UTRs of both major isoforms of
GNAL (ENST00000334049 and ENST00000423027).
We identified only two novel single nucleotide variations
in GNAL in three individuals in our case cohort. The first
was a missense mutation in exon 2 of the gene
(cDNA.1053C>T; P149S in ENST00000334049) that was
detected in one individual with onset of cervical dystonia in
the 4th decade, with a similarly affected father, suggesting
autosomal dominant inheritance. However, segregation
analysis revealed the variant had in fact been inherited from
his unaffected mother and was also present in his unaffected
brother (see Fig. 1A), ruling it out as the cause of the dysto-
nia in this family. The second variant, located in the 5
0
UTR
of isoform 2 (cDNA.199C>T in ENST00000423027), was
found in two individuals in our cohort exhibiting onset of
cervical dystonia in the 6th decade. One individual was a
sporadic case whereas the other was part of family with
multiple affected members (see Fig. 1B-C). Despite affecting
a highly conserved base (PhyloP score 5 4.158), the variant
failed to segregate with disease in the family, being absent in
two affected individuals (see Fig. 1C).
In summary, we did not identify any mutations in GNAL
that could be a cause of the dystonia in 192 cases drawn from
the United Kingdom, including 84 familial cases. Our own
data suggest that GNAL mutations do not represent a common
cause of dystonia — in the U.K. population at least — and that
the overall frequency of GNAL mutations may be closer to the
figure obtained by Vemula et al
2
than the 15% initially
reported by Fuchs et al.
1
This study also emphasises the impor-
tance of segregation analysis in establishing the pathogenicity
or otherwise of novel variants and suggests that other novel
genetic causes of dystonia remain to be identified.
Gavin Charlesworth, MRCP,
1
Kailash P. Bhatia, FRCP,
2
Nicholas W. Wood, FRCP
1
1
Department of Molecular Neuroscience, UCL Institute of
Neurology, Queen Square, London, UK.
2
Sobell Department of Motor Neuroscience and Movement
Disorders, UCL Institute of Neurology, Queen Square,
London, UK.
References
1. Fuchs T, Saunders-Pullman R, Masuho I, et al. Mutations in GNAL
cause primary torsion dystonia. Nature Genetics 2012;45:88-92.
2. Vemula SR, Puschmann A, Xiao J, et al. Role of Galpha(olf) in
familial and sporadic adult-onset primary dystonia. Hum Mol
Genet 2013;22:2510-2519.
FIG. 1. Family trees for individuals with novel variants in GNAL.Genetic
pedigrees for individuals with novel variants in GNAL. Affected family
members are marked by shaded symbols. The variant found is indi-
cated under the pedigree with transcript ID. Mutational status is indi-
cated by ‘m’ for heterozygous mutation carriers and ‘wt’ for
homozygous wildtype alleles. Index cases included in the initial
screening are marked with an asterisk.
LETTERS: NEW OBSERVATIONS
Movement Disorders, Vol. 29, No. 1, 2014 155
... The sequence variants identified vary greatly and include in-frame deletions, frameshifts, missense, nonsense, splice-site mutations, and variants that are predicted to result in nonsense-mediated decay. Mutation analysis programs (e.g., polymorphism phenotyping v2 (PolyPhen2), sorting intolerant from tolerant (SIFT), and mutation taster) are being used to examine the potential pathogenicity of GNAL variants in silico (Fuchs et al., 2013;Vemula et al., 2013;Charlesworth et al., 2014;Dobricic et al., 2014;Kumar et al., 2014;Zech et al., 2014;Ziegan et al., 2014). Concordance between all three programs and the absence of the variant in ethnically matched control groups is an indicator of likely pathogenicity of newly identified variants. ...
... Concordance between all three programs and the absence of the variant in ethnically matched control groups is an indicator of likely pathogenicity of newly identified variants. Although infrequent, GNAL mutations fill a critical lack of insight on the genetic basis for adult-onset focal dystonia (Charlesworth et al., 2014;Zech et al., 2014). ...
Inherited dystonias: clinical features and molecular pathways
Chapter
  • Jan 2018
Recent decades have witnessed dramatic increases in understanding of the genetics of dystonia - a movement disorder characterized by involuntary twisting and abnormal posture. Hampered by a lack of overt neuropathology, researchers are investigating isolated monogenic causes to pinpoint common molecular mechanisms in this heterogeneous disease. Evidence from imaging, cellular, and murine work implicates deficiencies in dopamine neurotransmission, transcriptional dysregulation, and selective vulnerability of distinct neuronal populations to disease mutations. Studies of genetic forms of dystonia are also illuminating the developmental dependence of disease symptoms that is typical of many forms of the disease. As understanding of monogenic forms of dystonia grows, a clearer picture will develop of the abnormal motor circuitry behind this relatively common phenomenology. This chapter focuses on the current data covering the etiology and epidemiology, clinical presentation, and pathogenesis of four monogenic forms of isolated dystonia: DYT-TOR1A, DYT-THAP1, DYT-GCH1, and DYT-GNAL.
View
... American (Vemula et al., 2013), Asian (Kumar et al., 2014;Vemula et al., 2013;Miao et al., 2013), and Serbian From Tolerant (SIFT), and Mutation Taster) are being used to examine in silico the potential pathogenicity of GNAL variants Fuchs et al., 2013;Vemula et al., 2013;Ziegan et al., 2014;Zech et al., 2014;Kumar et al., 2014;Charlesworth et al., 2014). Concordance between all three programs and the absence of the variant in ethnically matched control groups is an indicator of likely pathogenicity of newly identified variants. ...
... Concordance between all three programs and the absence of the variant in ethnically matched control groups is an indicator of likely pathogenicity of newly identified variants. Although infrequent, GNAL mutations fill a critical lack of insight on the genetic basis for adult-onset focal dystonia (Charlesworth et al., 2014;Zech et al., 2014). ...
Moving Towards Answers for DYT1 Dystonia: Development and Application of In Vivo and In Vitro Approaches to Elucidate Disease Pathogenesis.
Article
  • Jan 2015
Isolated primary dystonia describes a group of inherited movement disorders characterized by sustained muscle contractions traditionally thought to manifest in the absence of neurodegeneration. The most common form, DYT1 Dystonia, is caused by a dominant mutation in the gene TOR1A. This mutation is a 3 base pair in-frame deletion that results in the loss of a single glutamic acid ?????E??? from the encoded protein, torsinA. Understanding loss-of-function (LOF) and gain-of-function (GOF) properties of the ??E mutation is critical for defining disease mechanisms and developing future therapeutics. To evaluate the pathogenesis of ??E-torsinA in vivo I generated a novel conditional knockin mouse model that allows for anatomical- and temporal-specific expression of ??E-Tor1a via Cre recombination. I evaluated viability, neuropathology, and motor phenotypes of CNS-specific Tor1ai-??E/- and Tor1ai-??E/i-??E littermates and found no evidence for ??E GOF toxicity. Additionally, I demonstrated the power of this model by addressing a popular circuit level hypothesis in our field: cerebellar dysfunction explains reduced penetrance of DYT1 dystonia. I found that hindbrain specific induction of the DYT1 genotype is not sufficient to produce a mouse with an abnormal motor behavior. These in vivo findings support strictly LOF effects for the ??E mutation at the molecular and circuit level. TorsinA LOF mouse models reveal that discrete sensorimotor nuclei experience neural toxicity, evidence of altered protein quality control, and cell death. With this knowledge, I developed and characterized an in vitro cortical neuron culture that recapitulates in vivo LOF phenotypes as well as cell-type specific susceptibility. Identification of a cortical subtype specifically vulnerable to torsinA LOF sheds light on mechanisms behind abnormal motor output observed in disease-manifesting mouse models, thus introducing new hypotheses for circuit dysfunction in DYT1 dystonia patients. Together these in vivo and in vitro approaches deliver new insights on the molecular consequences of torsinA dysfunction. These tools will be useful in future studies that aim to identify mechanisms underlying the unique vulnerability of discrete cell types to torsinA LOF and the impact of neural development on the manifestation of dystonia.
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... The prevalence of GNAL mutations in dystonia was initially reported as 15 % in a study that analyzed specific families [4]. However, studies conducted in European and Asian populations reported frequencies below 2.6 % [8][9][10]. Therefore, it is necessary to collect more data to determine the prevalence of GNAL variants, as well as to report novel variants with pathogenic potential in different populations. ...
... F133L). The prevalence of disruptive GNAL mutations in this cohort of dystonia patients was 1.09 %, which is consistent with those recently reported between 0.5 and 2.6 % among individuals of European and Asian ancestry [8][9][10][11]. In Brazilian patients, idiopathic dystonia associated with GNAL mutations is less frequent than dystonia associated with THAP1 (8.8 %) or TOR1A (2.6 %) mutations [3]. ...
Screening of GNAL variants in Brazilian patients with isolated dystonia reveals a novel mutation with partial loss of function
Article
Full-text available
  • Apr 2016
  • J NEUROL
GNAL was identified as a cause of dystonia in patients from North America, Europe and Asia. In this study, we aimed to investigate the prevalence of GNAL variants in Brazilian patients with dystonia. Ninety-one patients with isolated idiopathic dystonia, negative for THAP1 and TOR1A mutations, were screened for GNAL variants by Sanger sequencing. Functional characterization of the Gαolf protein variant was performed using the bioluminescence resonance energy transfer assay. A novel heterozygous nonsynonymous variant (p. F133L) was identified in a patient with cervical and laryngeal dystonia since the third decade of life, with no family history. This variant was not identified in healthy Brazilian controls and was not described in 63,000 exomas of the ExAC database. The F133L mutant exhibited significantly elevated levels of basal BRET and severely diminished amplitude of response elicited by dopamine, that both indicate substantial functional impairment of Gαolf in transducing receptor signals, which could be involved in dystonia pathophysiology. GNAL mutations are not a common cause of dystonia in the Brazilian population and have a lower prevalence than THAP1 and TOR1A mutations. We present a novel variant that results in partial Gαolf loss of function.
View
... GNAL mutations were originally identified in two families, and subsequent screening in different cohorts with familial or sporadic isolated dystonia identified further cases and confirmed them as a cause of dystonia in approximately 0.4%-1.7% of all cases [8][9][10][11][12][13][14]. Taken together with the negative results of further screenings, GNAL mutations seem to represent a significant albeit infrequent cause of isolated dystonia [15]. GNAL encodes a protein involved in olfactory signal transductions and in dopamine signalling [16]. ...
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Recent consensus on the definition, phenomenology and classification of dystonia centres around phenomenology and guides our diagnostic approach for the heterogeneous group of dystonias. Current terminology classifies conditions where dystonia is the sole motor feature (apart from tremor) as ‘isolated dystonia’, while ‘combined dystonia’ refers to dystonias with other accompanying movement disorders. This review highlights recent advances in the genetics of some isolated and combined dystonic syndromes. Some genes, such as ANO3, GNAL and CIZ1, have been discovered for isolated dystonia, but they are probably not a common cause of classic cervical dystonia. Conversely, the phenotype associated with TUBB4A mutations expanded from that of isolated dystonia to a syndrome of hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC syndrome). Similarly, ATP1A3 mutations cause a wide phenotypic spectrum ranging from rapid-onset dystonia-parkinsonism to alternating hemiplegia of childhood. Other entities entailing dystonia-parkinsonism include dopamine transporter deficiency syndrome (SLC63 mutations); dopa-responsive dystonias; young-onset parkinsonism (PARKIN, PINK1 and DJ-1 mutations); PRKRA mutations; and X-linked TAF1 mutations, which rarely can also manifest in women. Clinical and genetic heterogeneity also characterizes myoclonus-dystonia, which includes not only the classical phenotype associated with epsilon-sarcoglycan mutations but rarely also presentation of ANO3 gene mutations, TITF1 gene mutations typically underlying benign hereditary chorea, and some dopamine synthesis pathway conditions due to GCH1 and TH mutations. Thus, new genes are being recognized for isolated dystonia, and the phenotype of known genes is broadening and now involves different combined dystonia syndromes.
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Unusual Movement Disorders
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In this chapter, we review unusual disorders with varied and complex phenomenologies. Many of these conditions are exceedingly rare, and some are actionable with negative consequences for the patient if missed. We have found that many trainees and even fellowship-trained movements disorder neurologists may have difficulty making these diagnoses with confidence. For this reason, we have chosen to group unusual movement disorder patients together, to enhance recognition and aid in management.
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Genetics of Dystonia
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  • Jan 2015
Great advances have been made in the field of dystonia in the last decade. This includes the identification of several new genes, and it is likely the number of known genetic causes will continue to grow. Currently 25 DYT loci have been allocated, most of them referring to autosomal dominantly inherited conditions or pure or complex dystonia. In this chapter we discuss genetic causes of dystonia with focus on those variants which have been assigned a DYT locus. We summarize main clinical findings and genetic underpinnings and give a brief discussion of a clinical approach.
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GNAL mutations and dystonia
Article
  • Aug 2014
  • ARCH NEUROL-CHICAGO
To the Editor We read with great interest the article by Kumar and colleagues¹ published in JAMA Neurology. They screened 318 patients with different types of dystonia, mainly sporadic, from Germany, Serbia, and Japan for mutations in all 12 exons of GNAL and found 2 putative mutations (c.637G>A and c.1057G>A) in 2 sporadic cases with craniocervical dystonia and cervical dystonia, respectively. The prevalence estimate of GNAL cases according to their figure is 0.62%, which is much lower than originally reported.² The initial discovery report by Fuchs et al² reported GNAL mutations in 6 of 39 families screened (approximately 15%). However, in the subsequent study by Vemula et al,³ only 3 GNAL mutations were detected in 760 individuals with familial or sporadic primary dystonia (<0.5%). Furthermore, a number of groups have subsequently screened different cohorts of patients with dystonia for GNAL mutations, yielding conflicting prevalence estimates (Table).
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Dystonia: An update on phenomenology, classification, pathogenesis and treatment
Article
  • Jun 2014
  • CURR OPIN NEUROL
Purpose of review: This article will highlight recent advances in dystonia with focus on clinical aspects such as the new classification, syndromic approach, new gene discoveries and genotype-phenotype correlations. Broadening of phenotype of some of the previously described hereditary dystonias and environmental risk factors and trends in treatment will be covered. Recent findings: Based on phenomenology, a new consensus update on the definition, phenomenology and classification of dystonia and a syndromic approach to guide diagnosis have been proposed. Terminology has changed and 'isolated dystonia' is used wherein dystonia is the only motor feature apart from tremor, and the previously called heredodegenerative dystonias and dystonia plus syndromes are now subsumed under 'combined dystonia'. The recently discovered genes ANO3, GNAL and CIZ1 appear not to be a common cause of adult-onset cervical dystonia. Clinical and genetic heterogeneity underlie myoclonus-dystonia, dopa-responsive dystonia and deafness-dystonia syndrome. ALS2 gene mutations are a newly recognized cause for combined dystonia. The phenotypic and genotypic spectra of ATP1A3 mutations have considerably broadened. Two new genome-wide association studies identified new candidate genes. A retrospective analysis suggested complicated vaginal delivery as a modifying risk factor in DYT1. Recent studies confirm lasting therapeutic effects of deep brain stimulation in isolated dystonia, good treatment response in myoclonus-dystonia, and suggest that early treatment correlates with a better outcome. Summary: Phenotypic classification continues to be important to recognize particular forms of dystonia and this includes syndromic associations. There are a number of genes underlying isolated or combined dystonia and there will be further new discoveries with the advances in genetic technologies such as exome and whole-genome sequencing. The identification of new genes will facilitate better elucidation of pathogenetic mechanisms and possible corrective therapies.
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Recent Advances in the Genetics of Dystonia
Article
  • Aug 2014
Dystonia, a common and genetically heterogeneous neurological disorder, was recently defined as "a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both." Via the application of whole-exome sequencing, the genetic landscape of dystonia and closely related movement disorders is becoming exposed. In particular, several "novel" genetic causes have been causally associated with dystonia or dystonia-related disorders over the past 2 years. These genes include PRRT2 (DYT10), CIZ1 (DYT23), ANO3 (DYT24), GNAL (DYT25), and TUBB4A (DYT4). Despite these advances, major gaps remain in identifying the genetic origins for most cases of adult-onset isolated dystonia. Furthermore, model systems are needed to study the biology of PRRT2, CIZ1, ANO3, Gαolf, and TUBB4A in the context of dystonia. This review focuses on these recent additions to the family of dystonia genes, genotype-phenotype correlations, and possible cellular contributions of the encoded proteins to the development of dystonia.
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Role of Gα(olf) in Familial and Sporadic Adult-Onset Primary Dystonia.
Article
Full-text available
  • Feb 2013
  • HUM MOL GENET
The vast majority of patients with primary dystonia are adults with focal or segmental distribution of involuntary movements. Although ∼10% of probands have at least one first- or second-degree relative to dystonia, large families suited for linkage analysis are exceptional. After excluding mutations in known primary dystonia genes (TOR1A, THAP1 and CIZ1), whole-exome sequencing identified a GNAL missense mutation (c.682G>T, p.V228F) in an African-American pedigree with clinical phenotypes that include cervical, laryngeal and hand-forearm dystonia. Screening of 760 subjects with familial and sporadic primary dystonia identified three Caucasian pedigrees with GNAL mutations [c.591dupA (p.R198Tfs*13); c.733C>T (p.R245*); and c.3G>A (p.M1?)]. These mutations show incomplete penetrance. Our findings corroborate those of a recent study which used whole-exome sequencing to identify missense and nonsense GNAL mutations in Caucasian pedigrees of mixed European ancestry with mainly adult-onset cervical and segmental dystonia. GNAL encodes guanine nucleotide-binding protein G(olf), subunit alpha [Gα(olf)]. Gα(olf) plays a role in olfaction, coupling D1 and A2a receptors to adenylyl cyclase, and histone H3 phosphorylation. African-American subjects harboring the p.V228F mutation exhibited microsmia. Lymphoblastoid cell lines from subjects with the p.V228F mutation showed upregulation of genes involved in cell cycle control and development. Consistent with known sites of network pathology in dystonia, immunohistochemical studies indicated that Gα(olf) is highly expressed in the striatum and cerebellar Purkinje cells, and co-localized with corticotropin-releasing hormone receptors in the latter.
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Mutations in GNAL cause primary torsion dystonia
Article
Full-text available
  • Dec 2012
  • Nat Genet
Dystonia is a movement disorder characterized by repetitive twisting muscle contractions and postures. Its molecular pathophysiology is poorly understood, in part owing to limited knowledge of the genetic basis of the disorder. Only three genes for primary torsion dystonia (PTD), TOR1A (DYT1), THAP1 (DYT6) and CIZ1 (ref. 5), have been identified. Using exome sequencing in two families with PTD, we identified a new causative gene, GNAL, with a nonsense mutation encoding p.Ser293* resulting in a premature stop codon in one family and a missense mutation encoding p.Val137Met in the other. Screening of GNAL in 39 families with PTD identified 6 additional new mutations in this gene. Impaired function of several of the mutants was shown by bioluminescence resonance energy transfer (BRET) assays.
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De novo mutations in ATP1A3 cause alternating hemiplegia of childhood
Article
Full-text available
  • Jul 2012
  • Nat Genet
Alternating hemiplegia of childhood (AHC) is a rare, severe neurodevelopmental syndrome characterized by recurrent hemiplegic episodes and distinct neurological manifestations. AHC is usually a sporadic disorder and has unknown etiology. We used exome sequencing of seven patients with AHC and their unaffected parents to identify de novo nonsynonymous mutations in ATP1A3 in all seven individuals. In a subsequent sequence analysis of ATP1A3 in 98 other patients with AHC, we found that ATP1A3 mutations were likely to be responsible for at least 74% of the cases; we also identified one inherited mutation in a case of familial AHC. Notably, most AHC cases are caused by one of seven recurrent ATP1A3 mutations, one of which was observed in 36 patients. Unlike ATP1A3 mutations that cause rapid-onset dystonia-parkinsonism, AHC-causing mutations in this gene caused consistent reductions in ATPase activity without affecting the level of protein expression. This work identifies de novo ATP1A3 mutations as the primary cause of AHC and offers insight into disease pathophysiology by expanding the spectrum of phenotypes associated with mutations in ATP1A3.
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Heterozygous de-novo mutations in ATP1A3 in patients with alternating hemiplegia of childhood: A whole-exome sequencing gene-identification study
Article
  • Jul 2012
Alternating hemiplegia of childhood (AHC) is a rare neurological disorder characterised by early-onset episodes of hemiplegia, dystonia, various paroxysmal symptoms, and developmental impairment. Almost all cases of AHC are sporadic but AHC concordance in monozygotic twins and dominant transmission in a family with a milder phenotype have been reported. Thus, we aimed to identify de-novo mutations associated with this disease. We recruited patients with clinically characterised AHC from paediatric neurology departments in Germany and with the aid of a parental support group between Sept, 2004, and May 18, 2012. We used whole-exome sequencing of three proband-parent trios to identify a disease-associated gene and then tested whether mutations in the gene were also present in the remaining patients and their healthy parents. We analysed genotypes and characterised their associations with the phenotypic spectrum of the disease. We studied 15 female and nine male patients with AHC who were aged 8-35 years. ATP1A3 emerged as the disease-associated gene in AHC. Whole-exome sequencing showed three heterozygous de-novo missense mutations. Sequencing of the 21 remaining affected individuals identified disease-associated mutations in ATP1A3 in all patients, including six de-novo missense mutations and one de-novo splice-site mutation. Because ATP1A3 is also the gene associated with rapid-onset dystonia-parkinsonism (DYT12, OMIM 128235) we compared the genotypes and phenotypes of patients with AHC in our cohort with those of patients with rapid-onset dystonia-parkinsonism reported in the scientific literature. We noted overlapping clinical features, such as abrupt onset of dystonic episodes often triggered by emotional stress, a rostrocaudal (face to arm to leg) gradient of involvement, and signs of brainstem dysfunction, as well as clearly differentiating clinical characteristics, such as episodic hemiplegia and quadriplegia. Mutation analysis of the ATP1A3 gene in patients who met clinical criteria for AHC allows for definite genetic diagnosis and sound genetic counselling. AHC and rapid-onset dystonia-parkinsonism are allelic diseases related to mutations in ATP1A3 and form a phenotypical continuum of a dystonic movement disorder. Eva Luise and Horst Köhler Foundation for Humans with Rare Diseases.
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