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Case Reports
. 2014 Mar 10;537(2):352-6.
doi: 10.1016/j.gene.2013.11.039. Epub 2013 Dec 17.

C19orf12 mutation leads to a pallido-pyramidal syndrome

Michael C Kruer  1 , Mustafa A Salih  2 , Catherine Mooney  3 , Jawahir Alzahrani  4 , Salah A Elmalik  5 , Mohammad M Kabiraj  6 , Arif O Khan  7 , Reema Paudel  8 , Henry Houlden  8 , Hamid Azzedine  9 , Fowzan Alkuraya  10
Affiliations
Case Reports

C19orf12 mutation leads to a pallido-pyramidal syndrome

Michael C Kruer et al. Gene. .

Abstract

Pallido-pyramidal syndromes combine dystonia with or without parkinsonism and spasticity as part of a mixed neurodegenerative disorder. Several causative genes have been shown to lead to pallido-pyramidal syndromes, including FBXO7, ATP13A2, PLA2G6, PRKN and SPG11. Among these, ATP13A2 and PLA2G6 are inconsistently associated with brain iron deposition. Using homozygosity mapping and direct sequencing in a multiplex consanguineous Saudi Arabian family with a pallido-pyramidal syndrome, iron deposition and cerebellar atrophy, we identified a homozygous p.G53R mutation in C19orf12. Our findings add to the phenotypic spectrum associated with C19orf12 mutations.

Keywords: BAER; CMAP; DML; ERG; MCV; MRI; Mb; Movement disorders; NBIA; Neurodegenerative disease; Neurogenetics; SNAP; VEP; base pairs; bp; brainstem auditory evoked response; compound motor action potential; distal motor latency; electroretinogram; magnetic resonance imaging; megabase; motor conduction velocity; neurodegeneration with brain iron accumulation; sensory nerve action potential; visual evoked potential.

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Figures

Figure 1
Figure 1. Index family
(A) Family pedigree. (B) Distal wasting of the upper limbs. Atrophy of the thenar and hypothenar muscles. (C) MRI features of affected individuals. MRI from patient 3 demonstrates T2 hypointensity of the globus pallidus, substantia nigra, and cerebellar atrophy consistent with Karak syndrome.
Figure 1
Figure 1. Index family
(A) Family pedigree. (B) Distal wasting of the upper limbs. Atrophy of the thenar and hypothenar muscles. (C) MRI features of affected individuals. MRI from patient 3 demonstrates T2 hypointensity of the globus pallidus, substantia nigra, and cerebellar atrophy consistent with Karak syndrome.
Figure 1
Figure 1. Index family
(A) Family pedigree. (B) Distal wasting of the upper limbs. Atrophy of the thenar and hypothenar muscles. (C) MRI features of affected individuals. MRI from patient 3 demonstrates T2 hypointensity of the globus pallidus, substantia nigra, and cerebellar atrophy consistent with Karak syndrome.
Figure 2
Figure 2. Catalog of C19orf12 mutations
Shown are reported mutations,–, including the present one based on UniProtKB Q9NSK7. Mutations cluster around the putative transmembrane region.
Figure 3
Figure 3. In silico analysis of the effect of p.G53R on protein binding regions, secondary structure, intrinsic disorder and transmembrane domain prediction
There is little change in the predicted secondary structure, protein disorder or short linear protein-binding motifs (SLiMs). Although some algorithms predicted no or small changes in the putative transmembrane (TM) region [MEMSAT-SVM/MEMSAT3 (magenta), PRO (cyan), PRODIV (blue), PolyPhobius (yellow), PHDhtm (orange), SMART/TMHMM (green), UniProt (red)], C19orf12 is annotated by Pfam as a glycine zipper-containing OmpA-like membrane domain. Glycine-zipper motifs (typically GxxxGxxxG repeats) strongly drive right-handed helix packing and mutations in the motif can block channel formation. The p.G53R mutation disrupts this important structural motif, possibly disrupting TM region architecture (as shown by changes in TM region prediction).
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References

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