Genetic and Functional Analyses of SHANK2 Mutations Suggest a Multiple Hit Model of Autism Spectrum Disorders
Figure 1
Genomic structure, isoforms, and expression of human SHANK2.
A. Genomic structure of the human SHANK2 gene. Transcription of SHANK2 produces four main mRNA from three distinct promoters: SHANK2E (AB208025), ProSAP1A (AB208026), ProSAP1 (AB208027) and AF141901. There are three translation starts: in exon 2 for SHANK2E, in exon1b for ProSAP1A, and in exon1c for ProSAP1 and AF141901; and two independent stop codons: in exon 22b for AF141901 and in exon 25 for SHANK2E, ProSAP1A and ProSAP1. Conserved domains of protein interaction or protein binding site are represented in color: ANK (red), SH3 (orange), PDZ (blue) and SAM (green), H (pink), D, (dark blue) and C (purple). Black stars identify the alternative spliced exons (‘brain-specific exons’ in turquoise: 19, 20 and 23). B. RT-PCRs of SHANK2 isoforms on RNA from different human control tissues (Clontech), and different brain regions of four controls (2 males and 2 females). The amplified regions specific to each isoform of SHANK2 are indicated by gray boxes. C. Alternative splicing of human SHANK2; exons 19, 20 and 23 are specific to the brain. ANK, ankyrin; SH3, Src homology 3; PDZ, PSD95/DLG/ZO1; SAM, sterile alpha motif; He, heart; Li, liver; B, brain; SM, skeletal muscle; Pl, placenta; K, kidney; Lu, lung; Pa, pancreas; FC, frontal cortex; Hi, hippocampus; TC, temporal cortex; T, thalamus; OC, occipital cortex; Ce, cerebellum; Cx, whole cortex; BLCL, B lymphoblastoid cell lines; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; BSR, brain specific region; H, homer binding site; D, dynamin binding site; C, cortactin binding site. The ages of the two males and the two females studied were 74, 42, 55, and 36 years with a post-mortem interval of 10, 21, 24, and 2 h, respectively.
