Dominant spinal muscular atrophy due to BICD2: a novel mutation refines the phenotype

Synofzik, Matthis; Martinez-Carrera, Lilian A.; Lindig, Tobias; Schöls, Lüdger; Wirth, Brunhilde

doi:10.1136/jnnp-2013-306777

Cited by 40 publications

(44 citation statements)

References 4 publications

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“…MRI of the legs in both patients displayed neurogenic muscular atrophy predominantly involving the quadriceps femoris, but sparing most of the other muscles of the thigh and lower leg. These findings are in good agreement with earlier work [5] and are similar to MRI findings observed in SMA-LED patients due to mutations in BICD2 [17–19]. This is particularly noteworthy as BICD2 , like DYNC1H1 , mediates specific minus end cargo transport along microtubules and has been linked to HSP [20].…”

Section: Discussionsupporting

confidence: 92%

Mutation screen reveals novel variants and expands the phenotypes associated with DYNC1H1

Strickland

Schabhüttl

Offenbacher³

et al. 2015

J Neurol

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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 (MCD), and Charcot-Marie-Tooth disease, type 2O (CMT2O). We hypothesized that additional variants could be found in these and novel motoneuron and related diseases. Therefore we analysed our database of 1,024 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.

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Section: Discussionsupporting

confidence: 92%

Mutation screen reveals novel variants and expands the phenotypes associated with DYNC1H1

Strickland

Schabhüttl

Offenbacher³

et al. 2015

J Neurol

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“…None of the three previously described SMA-LED families carrying mutations in BICD2 lying in the CC3 domain seemed to present with abnormal cortical development but this was not clearly documented with brain MRI [4][5][6]. Considering that cerebellar hypoplasia can run asymptomatically, we suggest further investigating this aspect in a larger group of genetically confirmed SMA-LED patients.…”

mentioning

confidence: 77%

Beyond spinal muscular atrophy with lower extremity dominance: cerebellar hypoplasia associated with a novel mutation in BICD2

Fiorillo

Moro

Brisca

et al. 2016

Euro J of Neurology

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“…Dominant mutations in DYNC1H1 (MIM #600112), encoding the dynein heavy chain, can cause spinal muscular atrophy with lower extremity predominance (SMA-LED1) [Harms et al, 2012;Tsurusaki et al, 2012], hereditary motor and sensory neuropathy (HMSN) [Weedon et al, 2011], malformations of cortical development [Vissers et al, 2010;Willemsen et al, 2012;Poirier et al, 2013], or a combined phenotype of motor neuron disease and cortical malformations [Fiorillo et al, 2014]. Mutations in the dynein adaptor BICD2 (MIM #609797) were recently found to cause SMA-LED2 and hereditary spastic paraplegia (HSP) [Neveling et al, 2013;Oates et al, 2013;Peeters et al, 2013;Synofzik et al, 2014], whereas mutations in other dynein adaptors, LIS1 (MIM #601545) and NDE1 (MIM #609449), affect brain development with lissencephaly as a result [Lo Nigro et al, 1997;Bakircioglu et al, 2011]. Finally, defects in dynactin (DCTN1; MIM #601143), a large multisubunit complex involved in most aspects of dynein function, cause distal hereditary motor neuropathy [Puls et al, 2003] and susceptibility to amyotrophic lateral sclerosis [Munch et al, 2004].…”

mentioning

confidence: 99%

Novel Mutations in the DYNC1H1 Tail Domain Refine the Genetic and Clinical Spectrum of Dyneinopathies

et al. 2015

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The heavy chain 1 of cytoplasmic dynein (DYNC1H1) is responsible for movement of the motor complex along microtubules and recruitment of dynein components. Mutations in DYNC1H1 are associated with spinal muscular atrophy (SMA), hereditary motor and sensory neuropathy (HMSN), cortical malformations, or a combination of these. Combining linkage analysis and whole-exome sequencing, we identified a novel dominant defect in the DYNC1H1 tail domain (c.1792C>T, p.Arg598Cys) causing axonal HMSN. Mutation analysis of the tail region in 355 patients identified a de novo mutation (c.791G>T, p.Arg264Leu) in an isolated SMA patient. Her phenotype was more severe than previously described, characterized by multiple congenital contractures and delayed motor milestones, without brain malformations. The mutations in DYNC1H1 increase the interaction with its adaptor BICD2. This relates to previous studies on BICD2 mutations causing a highly similar phenotype. Our findings broaden the genetic heterogeneity and refine the clinical spectrum of DYNC1H1, and have implications for molecular diagnostics of motor neuron diseases.

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Dominant spinal muscular atrophy due to BICD2: a novel mutation refines the phenotype

Cited by 40 publications

References 4 publications

Mutation screen reveals novel variants and expands the phenotypes associated with DYNC1H1

Mutation screen reveals novel variants and expands the phenotypes associated with DYNC1H1

Beyond spinal muscular atrophy with lower extremity dominance: cerebellar hypoplasia associated with a novel mutation in BICD2

Novel Mutations in the DYNC1H1 Tail Domain Refine the Genetic and Clinical Spectrum of Dyneinopathies

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