A Novel Homozygous Nonsense Variant in BICD2 Underlies Hereditary Spastic Paraplegia Complex Type
Sajida Rasool1, Saba Irshad1*, Neelam Saba1, Mehak Fiaz1, Muhammad Sajid Hussain2, MuhammadWajid Hussain3 and Peter Nürnberg2
Pedigree and clinical features. (A) Pedigree of family indicating second grade consanguinity and autosomal recessive mode of inheritance. Individuals with DNA samples available for genetic analyses are marked with asterisks. Arrowheads point to individual for whom whole exome sequencing was performed. (B) Clinical photographs of the affected members V-1 and V-2 showing stiffness and spasticity of upper as well as lower limbs and microcephalic feature.
Genome-wide scans for homozygous regions using 100K marker panel and multipoint LOD score graphs generated with ALLEGRO. Linkage region on chromosome 9 harboring BICD2 is indicated.
Mutation identification (A) BICD2 gene structure showing 7 exons. The mutation identified is indicated above in exon1, unfilled boxes at the start and end of the gene represents UTR regions. (B). BICD2 protein structure (855 amino acids). Domains are indicated by the specified color. N-terminal CC1 domain interacts with dynein-Dynactin complex, CC2 central domain interacts with kinesin protein and CC3 at C-terminal interacts with RAB6A, RNBAP2. Variants identified in HSP families so far are shown below, mutation identified in this study is in red, while text in black indicates variants identified earlier. (C). Chromatograms showing mutation in patient, heterozygous carrier along with wild type control.