Roles of the nebulin and β-tropomyosin genes in nemaline myopathy

...............................................................................................8 INTRODUCTION.......................................................................................10 REVIEW OF THE LITERATURE....................................................................11 1 Skeletal muscle................................................................................................................. 11 1.1 Development of skeletal muscle .............................................................................. 11 1.2 Structure of the sarcomere........................................................................................ 13 1.3 Function of the sarcomere ........................................................................................ 15 2 Sarcomeric proteins.......................................................................................................... 16 2.1 The thick filament protein myosin ........................................................................... 17 2.2 Thin filament proteins .............................................................................................. 18 2.2.1 Actin ................................................................................................................. 18 2.2.2 Nebulin and nebulette....................................................................................... 19 2.2.3 Tropomyosins................................................................................................... 20 2.2.4 Troponin ........................................................................................................... 21 2.2.5 Tropomodulin and CapZ .................................................................................. 22 2.3 Titin .......................................................................................................................... 23 2.4 Z-disc proteins.......................................................................................................... 24 2.4.1 α-Actinin .......................................................................................................... 24 2.4.2 Myopalladin ..................................................................................................... 25 2.4.3 Myotilin (myofibrillar protein with titin-like Ig domains)............................... 25 2.4.4 Desmin ............................................................................................................. 26 2.4.5 Other Z-disc associated proteins ...................................................................... 27 3 Nemaline myopathy ......................................................................................................... 29 3.1 Clinical features and classification........................................................................... 30 3.1.1 Severe congenital NM...................................................................................... 30 3.1.2 Intermediate congenital NM............................................................................. 30 3.1.3 Typical congenital NM..................................................................................... 31 3.1.4 Mild childhood or juvenile onset NM .............................................................. 31 3.1.5 Adult onset NM................................................................................................ 31 3.1.6 Other forms of NM........................................................................................... 32 3.2 Histological findings ................................................................................................ 32 3.3 Genes underlying NM .............................................................................................. 34 3.3.1 The γ-tropomyosin gene, TPM3....................................................................... 35 3.3.2 The nebulin gene, NEB..................................................................................... 36 3.3.3 The skeletal muscle α-actin gene, ACTA1........................................................ 37 3.3.4 The troponin T1 gene, TNNT1 ......................................................................... 39