Billy A. Watson and Kerby C. Oberg
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Defining the Number and Identity of Digits
A Turing-type model is now being used to describe how the number of
digits is determined in the autopod, as opposed to a simpler diffusion-gradient
type model of the polarizing agent, SHH (Sheth et al., 2012). Recent reports
show this periodic patterning model integrates an activator (BMP) and an
inhibitor (WNT) to specify a SOX9 expression pattern, which stimulates
chondrogenesis and dictates digit number (Raspopovic et al., 2014). BMPs
may play additional roles in defining digit identities by regulating SMADs and
the signal transduction pathways of the phalanx forming regions (Suzuki et al.,
2008).
Joint Formation
Disruption of genes integrally involved in muscle and joint development
also result in congenital anomalies of the limbs. Joint-development is under
the regulation of WNT proteins and growth and differentiation factor 5
(GDF5). In mice, a Gdf5 deficiency leads to brachypodism, an alteration in the
length and number of bones in the limb. The axial skeleton is not affected
(Storm et al., 1994). In humans, a missense mutation in the GDF5 gene leads
to multiple synostoses syndrome (Dawson et al., 2006), whereas
haploinsufficiency of the gene leads to brachydactyly (Polinkovsky et al.,
1997; Robin et al., 1997).
Arthogryposis in humans is classified as congenital joint contractures in
two or more areas of the body. Passive extension and flexion in the affected
joint or joints is negatively affected (Kalampokas et al., 2012). Arthogryposis
may be caused by environmental factors, but genetic etiologies are also well
established. Defects in muscle migration/formation, neuromuscular
connectivity, and general cell metabolism can impair joint movement.
Mutations in at least five genes (TNN12, TNNT3, TPM2, MYH3 and MYH8)
are associated with distal arthrogryposis (restricted movement of the hands and
feet) (Bamshad et al., 2009).
CLASSIFICATION
Increased knowledge in clinical genetics and the molecular basis of limb
development has aided clinicians and scientists to better define and classify the