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Case Reports
. 2014 Mar;35(3):298-302.
doi: 10.1002/humu.22491. Epub 2014 Jan 3.

Novel dynein DYNC1H1 neck and motor domain mutations link distal spinal muscular atrophy and abnormal cortical development

Chiara Fiorillo  1 , Francesca Moro, Julie Yi, Sarah Weil, Giacomo Brisca, Guja Astrea, Mariasavina Severino, Alessandro Romano, Roberta Battini, Andrea Rossi, Carlo Minetti, Claudio Bruno, Filippo M Santorelli, Richard Vallee
Affiliations
Case Reports

Novel dynein DYNC1H1 neck and motor domain mutations link distal spinal muscular atrophy and abnormal cortical development

Chiara Fiorillo et al. Hum Mutat. 2014 Mar.

Abstract

DYNC1H1 encodes the heavy chain of cytoplasmic dynein 1, a motor protein complex implicated in retrograde axonal transport, neuronal migration, and other intracellular motility functions. Mutations in DYNC1H1 have been described in autosomal-dominant Charcot-Marie-Tooth type 2 and in families with distal spinal muscular atrophy (SMA) predominantly affecting the legs (SMA-LED). Recently, defects of cytoplasmic dynein 1 were also associated with a form of mental retardation and neuronal migration disorders. Here, we describe two unrelated patients presenting a combined phenotype of congenital motor neuron disease associated with focal areas of cortical malformation. In each patient, we identified a novel de novo mutation in DYNC1H1: c.3581A>G (p.Gln1194Arg) in one case and c.9142G>A (p.Glu3048Lys) in the other. The mutations lie in different domains of the dynein heavy chain, and are deleterious to protein function as indicated by assays for Golgi recovery after nocodazole washout in patient fibroblasts. Our results expand the set of pathological mutations in DYNC1H1, reinforce the role of cytoplasmic dynein in disorders of neuronal migration, and provide evidence for a syndrome including spinal nerve degeneration and brain developmental problems.

Keywords: DYNC1H1; SMA-LED; abnormal cortical development; distal SMA.

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Conflict of interest statement

All authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Brain MRI examinations of Patient 1 (A–B) and Patient 2 (C–D), with corresponding normal control images (E–G) and muscle MRI examination of Patient 1 (H) and Patient 2 (I) at thigh and calf level Axial A) and right parasagittal B) 3D SPGR T1-weighted images show abnormal gyration and delicate PMG-like cortical malformation involving the insulae (white arrowheads) and Heschle gyri (white arrows) with abnormal vertical orientation of the posterior part of sylvian fissure (black arrow). C) Axial 3D TFE T1-weighted image reveals bilateral perisylvian PMG-like cortical malformation involving the insulae (white arrowheads) and Heschle gyri (white arrows). Note an additional area of abnormal cortical gyration with infolding (black arrows) in the right occipital lobe. D) Coronal 3D TFE T1-weighted image depicts another area of abnormal cortical gyration with infolding (black arrow) in the right posterior cingulum slightly deforming the right lateral ventricle. In muscle MRIs of lower limbs patients present diffuse atrophy and fat replacement of the thigh muscles which appear more prominent in Patient 2 (I), who accordingly displays the most severe phenotype. A selective similar sparing with compensatory hypertrophy of the adductor longus (al) and semitendinosus (st) muscles is evident to a similar extent in both cases. At leg level, MRI showed severe fat replacement of medial gastrocnemii (mg) with relative preservation of anterior tibialis (ta).
Figure 2
Figure 2
A–B Protein modeling A) Cartoon representation of secondary structure elements of the tail/linker region of cytoplasmic dynein 1 heavy chain 1 protein. The model exhibits the typical three helix fold of the spectrin repeat-domain (pfam00435) with the. Gln1194 residue (highlighted in red) located in the α-helix B. The box is shows a magnification of the region of interest with the predicted consequences of the replacement of Arginine for Glutamine at residue 1194. The effect of mutation on protein structure and stability, as predicted by Rosetta Backrub server and FoldX, is that it determines a change in the conformation of the α-helix B and decreases the global stability of the domain (ΔΔG: 4.66 ± 0.18 kcal/mol). B) Cartoon (left) and electrostatic surface (right) representations of wild-type (upper) and c.9142G>A (p.Glu3048Lys) (lower) AAA4-α/β submodule of human DYNC1H1 (residues 2870–3096). The AAA4-α/β domain exhibits the Rossmann-type fold with the Glu3048 residue located in the pre-Sensor I region (colored in red), the characteristic insert that extends from α-helix 3 and β-sheet 4 of the AAA4 module. The c.9142G>A (p.Glu3048Lys) mutation slightly decreases the global stability of the domain (ΔΔG: 1.06±0.08 kcal/mol) but severely alters the electrostatic surface of the pre-Sensor I region of AAA4 domain. Electrostatic surface potentials were colored according to charge with blue denoting positive charge (+5 kT/e-) and red, negative charge (−5 kT/e-). C–E Nocodazole washout experiments with cultured skin fibroblasts from patients 1 and 2 (yellow and green bars respectively) or a control individual (cyan bars) lacking the dynein mutations. Results are shown as percentage of cells from each cell line with bracketed numbers representing the number of cells examined. C) For all cell lines, at the time of nocodazole exposure, nearly 100% of cells had a fully disrupted Golgi. D) At 30 minutes after nocodazole washout, a higher percentage of cells from patients 1 and 2, as compared to control cells, showed a fully disrupted Golgi. E) At 90 minutes after nocodazole washout, the percentage of cells with a fully disrupted Golgi was higher in patient cells compared to control cells. This was particularly evident in patient 2, where the number of cells retaining a fully disrupted Golgi was nearly 50% of the total. Results are taken from at least 3 Independent experiments. Error bars=standard deviation; n= number of cells. Unpaired t-test: *, p<0.05 **, p<0.001. F. Representative images of cultured skin fibroblasts with intact (upper panel), partially disrupted (middle panel) and fully disrupted (lower panel) Golgi are shown. Golgi is stained in red. Scale bars=5μm.
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