Abstract
Dynein, cytoplasmic 1, heavy chain 1 (DYNC1H1) encodes a necessary subunit of the cytoplasmic dynein complex, which traffics cargo along microtubules. Dominant DYNC1H1 mutations are implicated in neural diseases, including spinal muscular atrophy with lower extremity dominance (SMA-LED), intellectual disability with neuronal migration defects, malformations of cortical development, and Charcot–Marie–Tooth disease, type 2O. We hypothesized that additional variants could be found in these and novel motoneuron and related diseases. Therefore, we analyzed our database of 1024 whole exome sequencing samples of motoneuron and related diseases for novel single nucleotide variations. We filtered these results for significant variants, which were further screened using segregation analysis in available family members. Analysis revealed six novel, rare, and highly conserved variants. Three of these are likely pathogenic and encompass a broad phenotypic spectrum with distinct disease clusters. Our findings suggest that DYNC1H1 variants can cause not only lower, but also upper motor neuron disease. It thus adds DYNC1H1 to the growing list of spastic paraplegia related genes in microtubule-dependent motor protein pathways.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2124-2134 |
| Number of pages | 11 |
| Journal | Journal of Neurology |
| Volume | 262 |
| Issue number | 9 |
| DOIs | |
| State | Published - Jun 24 2015 |
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Keywords
- DYNC1H1
- Epilepsy
- Gastric volvulus
- Peripheral neuropathy
- Spastic paraplegia
- Spinal muscular atrophy
ASJC Scopus subject areas
- Clinical Neurology
- Neurology
Cite this
Mutation screen reveals novel variants and expands the phenotypes associated with DYNC1H1. / Strickland, Alleene V.; Schabhüttl, Maria; Offenbacher, Hans; Synofzik, Matthis; Hauser, Natalie S.; Brunner-Krainz, Michaela; Gruber-Sedlmayr, Ursula; Moore, Steven A.; Windhager, Reinhard; Bender, Benjamin; Harms, Matthew; Klebe, Stephan; Young, Peter; Kennerson, Marina; Garcia, Avencia Sanchez Mejias; Gonzalez, Michael A.; Zuchner, Stephan L; Schule, Rebecca; Shy, Michael E.; Auer-Grumbach, Michaela.
In: Journal of Neurology, Vol. 262, No. 9, 24.06.2015, p. 2124-2134.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Mutation screen reveals novel variants and expands the phenotypes associated with DYNC1H1
AU - Strickland, Alleene V.
AU - Schabhüttl, Maria
AU - Offenbacher, Hans
AU - Synofzik, Matthis
AU - Hauser, Natalie S.
AU - Brunner-Krainz, Michaela
AU - Gruber-Sedlmayr, Ursula
AU - Moore, Steven A.
AU - Windhager, Reinhard
AU - Bender, Benjamin
AU - Harms, Matthew
AU - Klebe, Stephan
AU - Young, Peter
AU - Kennerson, Marina
AU - Garcia, Avencia Sanchez Mejias
AU - Gonzalez, Michael A.
AU - Zuchner, Stephan L
AU - Schule, Rebecca
AU - Shy, Michael E.
AU - Auer-Grumbach, Michaela
PY - 2015/6/24
Y1 - 2015/6/24
N2 - Dynein, cytoplasmic 1, heavy chain 1 (DYNC1H1) encodes a necessary subunit of the cytoplasmic dynein complex, which traffics cargo along microtubules. Dominant DYNC1H1 mutations are implicated in neural diseases, including spinal muscular atrophy with lower extremity dominance (SMA-LED), intellectual disability with neuronal migration defects, malformations of cortical development, and Charcot–Marie–Tooth disease, type 2O. We hypothesized that additional variants could be found in these and novel motoneuron and related diseases. Therefore, we analyzed our database of 1024 whole exome sequencing samples of motoneuron and related diseases for novel single nucleotide variations. We filtered these results for significant variants, which were further screened using segregation analysis in available family members. Analysis revealed six novel, rare, and highly conserved variants. Three of these are likely pathogenic and encompass a broad phenotypic spectrum with distinct disease clusters. Our findings suggest that DYNC1H1 variants can cause not only lower, but also upper motor neuron disease. It thus adds DYNC1H1 to the growing list of spastic paraplegia related genes in microtubule-dependent motor protein pathways.
AB - Dynein, cytoplasmic 1, heavy chain 1 (DYNC1H1) encodes a necessary subunit of the cytoplasmic dynein complex, which traffics cargo along microtubules. Dominant DYNC1H1 mutations are implicated in neural diseases, including spinal muscular atrophy with lower extremity dominance (SMA-LED), intellectual disability with neuronal migration defects, malformations of cortical development, and Charcot–Marie–Tooth disease, type 2O. We hypothesized that additional variants could be found in these and novel motoneuron and related diseases. Therefore, we analyzed our database of 1024 whole exome sequencing samples of motoneuron and related diseases for novel single nucleotide variations. We filtered these results for significant variants, which were further screened using segregation analysis in available family members. Analysis revealed six novel, rare, and highly conserved variants. Three of these are likely pathogenic and encompass a broad phenotypic spectrum with distinct disease clusters. Our findings suggest that DYNC1H1 variants can cause not only lower, but also upper motor neuron disease. It thus adds DYNC1H1 to the growing list of spastic paraplegia related genes in microtubule-dependent motor protein pathways.
KW - DYNC1H1
KW - Epilepsy
KW - Gastric volvulus
KW - Peripheral neuropathy
KW - Spastic paraplegia
KW - Spinal muscular atrophy
UR - http://www.scopus.com/inward/record.url?scp=84941997626&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84941997626&partnerID=8YFLogxK
U2 - 10.1007/s00415-015-7727-2
DO - 10.1007/s00415-015-7727-2
M3 - Article
C2 - 26100331
AN - SCOPUS:84941997626
VL - 262
SP - 2124
EP - 2134
JO - Journal of Neurology
JF - Journal of Neurology
SN - 0340-5354
IS - 9
ER -