two other duplications occurred. The first gave rise to DRP2, a common ancestor of dystrophin and utrophin, and to α- and β-dystrobrevin. The second resulted in the separate dystrophin and utrophin genes. In addition, sequence alignments of dystrophin family protein strongly support the concept that two distinct subfamilies exist, one consisted of dystrophin, utrophin, and DRP2 and the other consisted of α- and β-dystrobrevin. Classification Dystrobrevins are the product of two distinct genes coding for two highly homologous proteins, α- and β-dystrobrevin. Several different transcripts are derived from each gene by alternative splicing or initiation sites, generating a large family of dystrobrevin isoforms. Alpha Dystrobrevin The α-dystrobrevin structure is homologous to the cysteine-rich carboxy-terminal domain of dystrophin. This protein is expressed predominantly in skeletal muscle, heart, lung, and central nervous system. It is thought to be involved in synaptic transmission at the neuromuscular junction and in intracellular signaling. Beta Dystrobrevins The β-dystrobrevin, is only found in non-muscle tissues, predominantly expressed in kidney and brain, and forms complexes with dystrophin-associated proteins and syntrophin in liver and brain. In the brain, β-dystrobrevin associates with dystrophin isoforms in the cortex, hippocampus, and Purkinje neurons. Gene and transcripts The human α-dystrobrevin gene is localized to chromosome 18 and consists of 23 coding exons. α-Dystrobrevin is known to be subject to extensive splicing regulation. The alternative usage of three exons 21, 17B, and 11B generates RNA molecules with different lengths encoding three major α-dystrobrevin products in human skeletal muscle: α-dystrobrevin 1, α-dystrobrevin 2, and α-dystrobrevin 3. Due to alternative splicing within the coding regions, supplemental diversity is observed referred to as variable regions 1, 2, and 3 Firstly, variable region 1 (vr1) consists of a short exon containing three amino acids. In mice, the transcripts including this exon are primarily restricted to the brain but are present in the brain, heart, and skeletal muscle in humans. Secondly, variable region 2 (vr2) consists of exons 17A and 17B which encodes the unique C-terminal tail of α-dystrobrevin 2. Lastly, variable region 3 (vr3) consists of exons 11A, 11B, and 12, and exon 11B encodes the unique C-terminal tail of α-dystrobrevin 3. In mouse skeletal muscle, the splicing of vr2 and vr3 has been reported to be developmentally controlled. The human β-dystrobrevin gene was localized to the short arm of chromosome 2. Pair-wise comparison between α- and β-dystrobrevin sequences revealed that the two dystrobrevins have 76% identity. Structure