Myoclonus-dystonia: significance of large<i>SGCE</i>deletions

Grünewald, Anne; Djarmati, Ana; Lohmann-Hedrich, Katja; Farrell, Kevin; Zeller, Jack A.; Allert, Niels; Papengut, Frank; Petersen, Britt Sabina; Fung, Victor S.C.; Sue, Carolyn M.; O'sullivan, D. J.; Mahant, Neil; Kupsch, Andreas; Chuang, Rosalind; Wiegers, Karin; Pawlack, Heike; Hagenah, Johann; Ozelius, Laurie J.; Stephani, Ulrich; Schuit, Robert; Lang, Astrid; Volkmann, Jens; Münchau, Alexander; Klein, Christine

doi:10.1002/humu.9521

Cited by 106 publications

(120 citation statements)

References 38 publications

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“…4 About 50% of M-D patients who were classified as definite M-D carry a mutation in the widely expressed e-sarcoglycan (SGCE). [5][6][7] The genetic cause in the remaining patients is still unclear. A second locus has been reported in one large M-D family (DYT15, 18p11), but no gene has been identified yet.…”

Section: Myoclonus-dystonia (M-d) Is a Movement Disorder Characterizedmentioning

confidence: 99%

SGCE isoform characterization and expression in human brain: implications for myoclonus–dystonia pathogenesis?

et al. 2010

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Myoclonus-dystonia (M-D) is a neurological movement disorder with involuntary jerky and dystonic movements as major symptoms. About 50% of M-D patients have a mutation in e-sarcoglycan (SGCE), a maternally imprinted gene that is widely expressed. As little is known about SGCE function, one can only speculate about the pathomechanisms of the exclusively neurological phenotype in M-D. We characterized different SGCE isoforms in the human brain using ultra-deep sequencing. We show that a major brain-specific isoform is differentially expressed in the human brain with a notably high expression in the cerebellum, namely in the Purkinje cells and neurons of the dentate nucleus. Its expression was low in the globus pallidus and moderate to low in caudate nucleus, putamen and substantia nigra. Electrophysiological studies in man suggest that myoclonic symptoms are of subcortical origin. [1][2][3] In general, dystonia is thought to arise from dysfunction of the basal ganglia. 4 About 50% of M-D patients who were classified as definite M-D carry a mutation in the widely expressed e-sarcoglycan (SGCE). [5][6][7] The genetic cause in the remaining patients is still unclear. A second locus has been reported in one large M-D family (DYT15, 18p11), but no gene has been identified yet. 8,9 SGCE is part of the sarcoglycan family that consists of N-glycosylated transmembrane proteins. Six different sarcoglycans have been identified so far (a-, b-, g-, d-, e-and z-), but little is known about the function of particular sarcoglycan members and their function in different tissues. 10 In muscles, sarcoglycans form a heterotetrameric complex that is constituent of the dystrophinassociated protein complex. This complex mediates the structural stability of the plasma membrane and interactions between the extracellular matrix and the cytoskeleton. 11 Mutations in other sarcoglycans, a-, b-, g-and d-sarcoglycan, lead to different forms of limb-girdle muscular dystrophy, characterized by progressive muscle weakness. 10 Little is known about composition and function of the dystrophin-associated protein complex in the brain. SGCE is highly homologous to a-sarcoglycan, 12 but no muscle

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Section: Myoclonus-dystonia (M-d) Is a Movement Disorder Characterizedmentioning

confidence: 99%

SGCE isoform characterization and expression in human brain: implications for myoclonus–dystonia pathogenesis?

et al. 2010

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“…The first case of M-D due to complete paternal deletion of SGCE was published by DeBerardinis et al (2003). Four other cases with M-D and complete deletion of SGCE were recently described (Asmus et al 2007;Grünewald et al 2008). PEG10 is strongly expressed in the placenta and is essential for embryo development (Ono et al 2006).…”

Section: Discussionmentioning

confidence: 99%

“…However, COL1A2 haploinsufficiency could be implicated in very mild forms of osteogenesis imperfecta type I. Indeed, three patients have been previously reported (Asmus et al 2007;Grünewald et al 2008) with COL1A2 deletion and delayed skeletal development, osteoporosis, or joint problems. These data should guide the clinical follow-up to detect signs of bone and joint disease.…”

Section: Discussionmentioning

confidence: 99%

Cryptic 7q21 and 9p23 deletions in a patient with apparently balanced de novo reciprocal translocation t(7;9)(q21;p23) associated with a dystonia-plus syndrome: paternal deletion of the epsilon-sarcoglycan (SGCE) gene

et al. 2008

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We report on a boy with myoclonus-dystonia (M-D), language delay, and malformative anomalies. Genetic investigations allowed the identification of an apparently balanced de novo reciprocal translocation, t(7;9)(q21;p23). Breakpoint-region mapping using fluorescent in situ hybridization (FISH) analysis of bacterial artificial chromosome (BAC) clone probes identified microdeletions of 3.7 and 5.2 Mb within 7q21 and 9p23 breakpoint regions, respectively. Genotyping with microsatellite markers showed that deletions originated from paternal alleles. The deleted region on chromosome 7q21 includes a large imprinted gene cluster. SGCE and PEG10 are two maternally imprinted genes. SGCE mutations are implicated in M-D. In our case, M-D is due to deletion of the paternal allele of the SGCE gene. PEG10 is strongly expressed in the placenta and is essential for embryo development. Prenatal growth retardation identified in the patient may be due to deletion of the paternal allele of the PEG10 gene. Other genes in the deleted region on chromosome 7 are not imprinted. Nevertheless, a phenotype can be due to haploinsufficiency of these genes. KRIT1 is implicated in familial forms of cerebral cavernous malformations, and COL1A2 may be implicated in very mild forms of osteogenesis imperfecta. The deleted region on chromosome 9 overlaps with the candidate region for monosomy 9p syndrome. The proband shows dysmorphic features compatible with monosomy 9p syndrome, without mental impairment. These results emphasize that the phenotypic abnormalities of apparently balanced de novo translocations can be due to cryptic deletions and that the precise mapping of these aneusomies may improve clinical management.

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“…However, family history is positive in more than 80 % of cases with genetically confi rmed DYT11 dystonia [ 12 ]. Gene function remains unknown.…”

Section: Dyt11 (Myoclonus-dystonia) Associated With Sgce Gene Mutationsmentioning

confidence: 96%

“…Furthermore, routine methods may only involve mutational analysis, while for some genes mutational screening per se may not be suffi cient as entire or parts of genes may be deleted or multiplied (whole gene deletion, exon deletion, duplications, etc. ), also referred to as gene dosage alterations, e.g., in the context of dystonia in GTP cyclohydrolase [ 11 ] or SGCE [ 12 ]. These are only detected if gene dosage analysis is performed.…”

Section: Genetic Forms Of Dystoniamentioning

confidence: 98%

Genetics of Dystonia

Schneider

Bhatia

2015

Movement Disorder Genetics

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Great advances have been made in the fi eld of dystonia in the last decade. This includes the identifi cation 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 fi ndings and genetic underpinnings and give a brief discussion of a clinical approach. Keywords

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Myoclonus-dystonia: significance of largeSGCEdeletions

Cited by 106 publications

References 38 publications

SGCE isoform characterization and expression in human brain: implications for myoclonus–dystonia pathogenesis?

SGCE isoform characterization and expression in human brain: implications for myoclonus–dystonia pathogenesis?

Cryptic 7q21 and 9p23 deletions in a patient with apparently balanced de novo reciprocal translocation t(7;9)(q21;p23) associated with a dystonia-plus syndrome: paternal deletion of the epsilon-sarcoglycan (SGCE) gene

Genetics of Dystonia

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