Novel mutations in the DYNC1H1 tail domain refine the genetic and clinical spectrum of dyneinopathies.

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.

Mosaic dominant TUBB4A mutation in an inbred family with complicated hereditary spastic paraplegia.

BACKGROUND: Mutations in TUBB4A have been associated with a spectrum of neurological conditions, ranging from the severe hypomyelination with atrophy of the basal ganglia and cerebellum syndrome to the clinically milder dystonia type 4. The presence of movement abnormalities was considered the common hallmark of these disorders. METHODS: Clinical, neurological, and neuroimaging examinations, followed by whole exome sequencing and mutation analysis, were performed in a highly consanguineous pedigree with five affected children. RESULTS: We identified a novel c.568C>T (p.H190Y) TUBB4A mutation that originated de novo in the asymptomatic mother. The affected subjects presented with an early-onset, slowly progressive spastic paraparesis of the lower limbs, ataxia, and brain hypomyelination, in the absence of dystonia or rigidity. CONCLUSIONS: Our study adds complicated hereditary spastic paraplegia to the clinical spectrum of TUBB4A-associated neurological disorders. We establish genotype-phenotype correlations with mutations located in the same region in the tertiary structure of the protein.