Duchenne muscular dystrophy (DMD) and the allelic disorder Becker muscular
dystrophy (BMD) are common X-linked recessive neuromuscular disorders that
are associated with a spectrum of genetically based developmental cognitive
and behavioral disabilities. Seven promoters scattered throughout the huge
DMD/BMD gene locus normally code for distinct isoforms of the gene product
, dystrophin, that exhibit nervous system developmental, regional and cell-
type specificity. Dystrophin is a complex plasmalemmal-cytoskeletal linker
protein that possesses multiple functional domains, autosomal and X-linked
homologs and associated binding proteins that form multiunit signaling comp
lexes whose composition is unique to each cellular and developmental contex
t. Through additional interactions with a variety of proteins of the extrac
ellular matrix, plasma membrane, cytoskeleton and distinct intracelluar com
partments, brain dystrophin acquires the capability to participate in the m
odulatory actions of a large number of cellular signaling pathways. During
neural development, dystrophin is expressed within the neural tube and sele
cted areas of the embryonic and postnatal neuraxis, and may regulate distin
ct aspects of neurogenesis, neuronal migration and cellular differentiation
. By contrast, in the mature brain, dystrophin is preferentially expressed
by specific regional neuronal subpopulations within proximal somadendritic
microdomains associated with synaptic terminal membranes. Increasing experi
mental evidence suggests that in adult life, dystrophin normally modulates
synaptic terminal integrity, distinct forms of synaptic plasticity and regi
onal cellular signal integration. At a systems level, dystrophin may regula
te essential components of an integrated sensorimotor attentional network.
Dystrophin deficiency in DMD/BMD patients and in the mdx mouse model appear
s to impair intracellular calcium homeostasis and to disrupt multiple prote
in-protein interactions that normally promote information transfer and sign
al integration from the extracellular environment to the nucleus within reg
ulated microdomains. In DMD/BMD, the individual profiles of cognitive and b
ehavioral deficits, mental retardation and other phenotypic variations appe
ar to depend on complex profiles of transcriptional regulation associated w
ith individual dystrophin mutations that result in the corresponding presen
ce or absence of individual brain dystrophin isoforms that normally exhibit
developmental, regional and cell-type-specific expression and functional r
egulation. This composite experimental model will allow fine-level mapping
of cognitive-neurogenetic associations that encompass the interrelationship
s between molecular, cellular and systems levels of signal integration, and
will further our understanding of complex gene-environmental interactions
and the pathogenetic basis of developmental disorders associated with menta
l retardation. (C) 2000 Elsevier Science B.V. All rights reserved.