ClinVar Genomic variation as it relates to human health

Torsion Dystonia 1, Autosomal Dominant In cases of early-onset torsion dystonia (DYT1; 128100), Ozelius et al. (1997) identified a heterozygous 3-bp deletion, GAG (delE302/303), resulting in the loss of 1 of a pair of conserved glutamic acid residues in a novel ATP-binding protein termed torsin-A. The GAG deletion was the only mutation detected in a large number of patients from different ethnic backgrounds. Most (90%) patients with an atypical presentation had no identifiable mutation in the DYT1 gene. At least 4 different background haplotypes were observed with the GAG deletion, indicating that the mutation had arisen more than once to cause ITD. Given the highly variable phenotype and reduced penetrance observed in ITD, the identification of the DYT1 mutation was a major advance for accurate diagnosis of the disorder. Because this mutation deletes one of 2 contiguous glutamic acid codons of the DYT1 gene, Goodchild and Dauer (2004) and Naismith et al. (2004) referred to it as delE302/303. Ikeuchi et al. (1999) described the apparently sporadic occurrence of primary torsion dystonia in a 25-year-old Japanese man who first noted at age 13 years that his left shoulder occasionally turned involuntarily to the left. By age 16 years his neck also became involved, twisting involuntarily to the left like his shoulder. He showed moderate improvement with diazepam (20 mg) and trihexyphenidyl (18 mg). Neither parent and none of the 4 grandparents showed any movement disorder or complained of writer's cramp. Nucleotide sequence analysis detected the GAG deletion in the patient's DYT1 gene. Restriction fragment length polymorphism (RFLP) analysis using BseRI showed that the GAG deletion was present not only in the patient but also in his mother, but not in his father. Kamm et al. (1999) examined 57 patients with idiopathic torsion dystonia for the 3-bp GAG deletion in the DYT1 gene. Three of 5 patients with early limb-onset torsion dystonia, one of them with a positive family history, tested positive for the mutation, as did 1 young patient with multifocal dystonia and a short course of the disease. Two patients with early-onset generalized dystonia beginning in the cervical muscles, as well as 5 other patients with multifocal, 14 patients with segmental, and 30 patients with focal cervical dystonia did not carry the mutation. This suggested that the GAG deletion is responsible for most cases of typical early limb-onset dystonia, but not for other types of dystonia, in the German population studied. Hjermind et al. (2002) performed mutation analysis for the GAG deletion in the DYT1 gene in 107 unrelated Danish probands with primary torsion dystonia (37 were known familial cases). Clinical examinations showed that 22 probands had generalized dystonia (20 of whom had early limb-onset), 2 had hemidystonia, 5 had multifocal dystonia, 15 had segmental dystonia, and 63 had focal dystonia. Among the 107 probands investigated, the GAG deletion was only detected in 3 (2.8%) in whom the phenotype was typical. This corresponded to 15% of the 20 probands with early limb-onset generalized dystonia. Of the 3 probands with the GAG deletion, only 1 had familial dystonia, with the mutation detected in the affected father and in 6 asymptomatic adult relatives. In the second proband the DYT1 mutation was also encountered in the asymptomatic mother, while in the third case none of the parents had the GAG deletion and therefore represented a de novo mutation. Ikeuchi et al. (2002) studied 6 unrelated Japanese pedigrees with dystonia due to the GAG deletion in the DYT1 gene. None of the haplotypes in these families shared strong similarity to the Ashkenazi Jewish haplotype, suggesting that the GAG deletion occurred independently in the Japanese population. Some sharing was observed among haplotypes of the Japanese families, but there was nonetheless an indication of multiple independent events resulting in the deletion in these pedigrees. Among 256 patients with various subtypes of dystonia, Grundmann et al. (2003) identified 6 patients (2%) with the GAG deletion in the DYT1 gene. Two patients had classic features of early-onset primary generalized dystonia, 2 had multifocal dystonia (1 with involvement of cranial and cervical muscles), and 2 had only writer's cramp with slight progression. Apart from 1 patient with onset at 41 years, the mean age at onset was 9 years. Grundmann et al. (2003) emphasized the wide range of phenotypic variability caused by this DYT1 mutation. Wong et al. (2005) described a 10-year-old boy with the DYT1 deletion who had an unusual clinical presentation. At age 4 years, he presented with stiffness of the left ankle that progressed to the other leg. A year later he developed severe, painful myoclonic muscle spasms that were either spontaneous or precipitated by changes in posture, loud noises, or emotional upset, and were associated with profuse sweating. During these episodes, there was extreme truncal and limb stiffness and rigidity. EMG showed continuous motor unit activity during muscle spasms, suggestive of stiff-person syndrome (SPS; 184850), but no anti-GAD65 (138275) antibodies were found. He soon developed progressive dystonia and was wheelchair-bound by age 7 years. The patient experienced clinical improvement following plasmapheresis, which was unexplainable to the authors. His asymptomatic mother had the same DYT1 deletion, and a 13-year-old sister had type 1 diabetes mellitus (T1D; 222100) and was positive for anti-GAD65 antibodies. Wong et al. (2005) suggested a diagnosis of 'stiff-child syndrome,' but also considered that the patient may have had a phenotypic variation of primary torsion dystonia. Greene and Dauer (2006) suggested that the patient reported by Wong et al. (2005) had a severe form of DYT1 dystonia with painful limb dystonia. Arthrogryposis Multiplex Congenita 5 In 2 unrelated girls, each born of consanguineous Iranian parents (families 2 and 3), with arthrogryposis multiplex congenita-5 (AMC5; 618947), Kariminejad et al. (2017) identified a homozygous 3-bp deletion (c.907_909del) in the TOR1A gene, resulting in the deletion of glu303 (E303del). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. The variant is present in heterozygous state only in 30 of 282,658 alleles in the gnomAD database. None of the carrier parents had evidence of torsion dystonia, consistent with incomplete penetrance of the dominant phenotype. Functional studies of the variant and studies of patient cells were not performed. For discussion of the E303del mutation in the TOR1A gene, that was found in compound heterozygous state in a patient with AMC5 by Reichert et al. (2017), see 605204.0007. Variant Function Hewett et al. (2000) overexpressed wildtype and mutant (GAG-deleted) torsin-A in mouse neural CAD cells and observed the distribution pattern of the proteins by immunocytochemistry. The wildtype protein was found throughout the cytoplasm and neurites with a high degree of colocalization with the endoplasmic reticulum (ER) marker, protein disulfide isomerase. In contrast, the mutant protein accumulated in multiple, large inclusions in the cytoplasm around the nucleus. These inclusions were composed of membrane whorls, apparently derived from the ER. The authors hypothesized that if disrupted processing of the mutant protein leads to its accumulation in multilayer membranous structures in vivo, these may interfere with membrane trafficking in neurons. Most cases of early-onset torsion dystonia (EOTD) are caused by a deletion of 1 glutamic acid in the carboxyl terminus of the torsin-A protein. The mutation causes the protein to aggregate in perinuclear inclusions as opposed to the endoplasmic reticulum localization of the wildtype protein. There is evidence that dysfunction of the dopamine system is implicated in the development of EOTD. Torres et al. (2004) studied the biologic function of torsin-A and its relation to dopaminergic neurotransmission. They showed that torsin-A can regulate the cellular trafficking of the dopamine transporter (126455), as well as other polytopic membrane-bound proteins, including G protein-coupled receptors, transporters, and ion channels. This effect was prevented by mutating the ATP-binding site in torsin-A. The delta-Glu mutant causing dystonia did not have any effect on the cell surface distribution of polytopic membrane-associated proteins, suggesting that the mutation linked with EOTD results in a loss of function. However, a mutation in the ATP-binding site in delta-Glu-torsin-A reversed the aggregate phenotype associated with the mutant. Moreover, the deletion mutant acts as a dominant-negative of the wildtype torsin-A through a mechanism presumably involving association of wildtype and mutant protein. Taken together, these results provided evidence for a functional role of torsin-A and for a loss of function and a dominant-negative phenotype of the delta-Glu-torsin-A mutation. These properties may contribute to the autosomal dominant nature of EOTD. Chen et al. (2010) showed that expression of human TOR1A with the delta-E mutation in C. elegans induced an ER stress response, even in the absence of additional stressors. Furthermore, expression of delta-E TOR1A with wildtype TOR1A in worms abrogated the protective effect of wildtype TOR1A expression against tunicamycin- or dithiothreitol-induced ER stress. In vitro cellular expression studies by Hettich et al. (2014) indicated that the delE303 mutant protein had an increased tendency to dimerize in the absence of reducing conditions, caused reduced processing of several proteins through the intracellular secretory pathway, decreased neurite extension, and caused vacuolization and morphologic changes in the endoplasmic reticulum and nuclear envelope compared to wildtype. (less)

Torsion Dystonia 1, Autosomal Dominant In cases of early-onset torsion dystonia (DYT1; 128100), Ozelius et al. (1997) identified a heterozygous 3-bp deletion, GAG (delE302/303), resulting in the loss of 1 of a pair of conserved glutamic acid residues in a novel ATP-binding protein termed torsin-A. The GAG deletion was the only mutation detected in a large number of patients from different ethnic backgrounds. Most (90%) patients with an atypical presentation had no identifiable mutation in the DYT1 gene. At least 4 different background haplotypes were observed with the GAG deletion, indicating that the mutation had arisen more than once to cause ITD. Given the highly variable phenotype and reduced penetrance observed in ITD, the identification of the DYT1 mutation was a major advance for accurate diagnosis of the disorder. Because this mutation deletes one of 2 contiguous glutamic acid codons of the DYT1 gene, Goodchild and Dauer (2004) and Naismith et al. (2004) referred to it as delE302/303. Ikeuchi et al. (1999) described the apparently sporadic occurrence of primary torsion dystonia in a 25-year-old Japanese man who first noted at age 13 years that his left shoulder occasionally turned involuntarily to the left. By age 16 years his neck also became involved, twisting involuntarily to the left like his shoulder. He showed moderate improvement with diazepam (20 mg) and trihexyphenidyl (18 mg). Neither parent and none of the 4 grandparents showed any movement disorder or complained of writer's cramp. Nucleotide sequence analysis detected the GAG deletion in the patient's DYT1 gene. Restriction fragment length polymorphism (RFLP) analysis using BseRI showed that the GAG deletion was present not only in the patient but also in his mother, but not in his father. Kamm et al. (1999) examined 57 patients with idiopathic torsion dystonia for the 3-bp GAG deletion in the DYT1 gene. Three of 5 patients with early limb-onset torsion dystonia, one of them with a positive family history, tested positive for the mutation, as did 1 young patient with multifocal dystonia and a short course of the disease. Two patients with early-onset generalized dystonia beginning in the cervical muscles, as well as 5 other patients with multifocal, 14 patients with segmental, and 30 patients with focal cervical dystonia did not carry the mutation. This suggested that the GAG deletion is responsible for most cases of typical early limb-onset dystonia, but not for other types of dystonia, in the German population studied. Hjermind et al. (2002) performed mutation analysis for the GAG deletion in the DYT1 gene in 107 unrelated Danish probands with primary torsion dystonia (37 were known familial cases). Clinical examinations showed that 22 probands had generalized dystonia (20 of whom had early limb-onset), 2 had hemidystonia, 5 had multifocal dystonia, 15 had segmental dystonia, and 63 had focal dystonia. Among the 107 probands investigated, the GAG deletion was only detected in 3 (2.8%) in whom the phenotype was typical. This corresponded to 15% of the 20 probands with early limb-onset generalized dystonia. Of the 3 probands with the GAG deletion, only 1 had familial dystonia, with the mutation detected in the affected father and in 6 asymptomatic adult relatives. In the second proband the DYT1 mutation was also encountered in the asymptomatic mother, while in the third case none of the parents had the GAG deletion and therefore represented a de novo mutation. Ikeuchi et al. (2002) studied 6 unrelated Japanese pedigrees with dystonia due to the GAG deletion in the DYT1 gene. None of the haplotypes in these families shared strong similarity to the Ashkenazi Jewish haplotype, suggesting that the GAG deletion occurred independently in the Japanese population. Some sharing was observed among haplotypes of the Japanese families, but there was nonetheless an indication of multiple independent events resulting in the deletion in these pedigrees. Among 256 patients with various subtypes of dystonia, Grundmann et al. (2003) identified 6 patients (2%) with the GAG deletion in the DYT1 gene. Two patients had classic features of early-onset primary generalized dystonia, 2 had multifocal dystonia (1 with involvement of cranial and cervical muscles), and 2 had only writer's cramp with slight progression. Apart from 1 patient with onset at 41 years, the mean age at onset was 9 years. Grundmann et al. (2003) emphasized the wide range of phenotypic variability caused by this DYT1 mutation. Wong et al. (2005) described a 10-year-old boy with the DYT1 deletion who had an unusual clinical presentation. At age 4 years, he presented with stiffness of the left ankle that progressed to the other leg. A year later he developed severe, painful myoclonic muscle spasms that were either spontaneous or precipitated by changes in posture, loud noises, or emotional upset, and were associated with profuse sweating. During these episodes, there was extreme truncal and limb stiffness and rigidity. EMG showed continuous motor unit activity during muscle spasms, suggestive of stiff-person syndrome (SPS; 184850), but no anti-GAD65 (138275) antibodies were found. He soon developed progressive dystonia and was wheelchair-bound by age 7 years. The patient experienced clinical improvement following plasmapheresis, which was unexplainable to the authors. His asymptomatic mother had the same DYT1 deletion, and a 13-year-old sister had type 1 diabetes mellitus (T1D; 222100) and was positive for anti-GAD65 antibodies. Wong et al. (2005) suggested a diagnosis of 'stiff-child syndrome,' but also considered that the patient may have had a phenotypic variation of primary torsion dystonia. Greene and Dauer (2006) suggested that the patient reported by Wong et al. (2005) had a severe form of DYT1 dystonia with painful limb dystonia. Arthrogryposis Multiplex Congenita 5 In 2 unrelated girls, each born of consanguineous Iranian parents (families 2 and 3), with arthrogryposis multiplex congenita-5 (AMC5; 618947), Kariminejad et al. (2017) identified a homozygous 3-bp deletion (c.907_909del) in the TOR1A gene, resulting in the deletion of glu303 (E303del). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. The variant is present in heterozygous state only in 30 of 282,658 alleles in the gnomAD database. None of the carrier parents had evidence of torsion dystonia, consistent with incomplete penetrance of the dominant phenotype. Functional studies of the variant and studies of patient cells were not performed. For discussion of the E303del mutation in the TOR1A gene, that was found in compound heterozygous state in a patient with AMC5 by Reichert et al. (2017), see 605204.0007. Variant Function Hewett et al. (2000) overexpressed wildtype and mutant (GAG-deleted) torsin-A in mouse neural CAD cells and observed the distribution pattern of the proteins by immunocytochemistry. The wildtype protein was found throughout the cytoplasm and neurites with a high degree of colocalization with the endoplasmic reticulum (ER) marker, protein disulfide isomerase. In contrast, the mutant protein accumulated in multiple, large inclusions in the cytoplasm around the nucleus. These inclusions were composed of membrane whorls, apparently derived from the ER. The authors hypothesized that if disrupted processing of the mutant protein leads to its accumulation in multilayer membranous structures in vivo, these may interfere with membrane trafficking in neurons. Most cases of early-onset torsion dystonia (EOTD) are caused by a deletion of 1 glutamic acid in the carboxyl terminus of the torsin-A protein. The mutation causes the protein to aggregate in perinuclear inclusions as opposed to the endoplasmic reticulum localization of the wildtype protein. There is evidence that dysfunction of the dopamine system is implicated in the development of EOTD. Torres et al. (2004) studied the biologic function of torsin-A and its relation to dopaminergic neurotransmission. They showed that torsin-A can regulate the cellular trafficking of the dopamine transporter (126455), as well as other polytopic membrane-bound proteins, including G protein-coupled receptors, transporters, and ion channels. This effect was prevented by mutating the ATP-binding site in torsin-A. The delta-Glu mutant causing dystonia did not have any effect on the cell surface distribution of polytopic membrane-associated proteins, suggesting that the mutation linked with EOTD results in a loss of function. However, a mutation in the ATP-binding site in delta-Glu-torsin-A reversed the aggregate phenotype associated with the mutant. Moreover, the deletion mutant acts as a dominant-negative of the wildtype torsin-A through a mechanism presumably involving association of wildtype and mutant protein. Taken together, these results provided evidence for a functional role of torsin-A and for a loss of function and a dominant-negative phenotype of the delta-Glu-torsin-A mutation. These properties may contribute to the autosomal dominant nature of EOTD. Chen et al. (2010) showed that expression of human TOR1A with the delta-E mutation in C. elegans induced an ER stress response, even in the absence of additional stressors. Furthermore, expression of delta-E TOR1A with wildtype TOR1A in worms abrogated the protective effect of wildtype TOR1A expression against tunicamycin- or dithiothreitol-induced ER stress. In vitro cellular expression studies by Hettich et al. (2014) indicated that the delE303 mutant protein had an increased tendency to dimerize in the absence of reducing conditions, caused reduced processing of several proteins through the intracellular secretory pathway, decreased neurite extension, and caused vacuolization and morphologic changes in the endoplasmic reticulum and nuclear envelope compared to wildtype. (less)