537by using genomic capture and DNA sequencing (Jordan et al. 2012 ). The mutations
altered splicing between CARD14 exons 3 and 4. CARD14 activates nuclear factor
kappa B (NF-kB), and compared with wild-type CARD14, the p.Gly117Ser and
p.Glu138Ala substitutions were shown to lead to enhanced NF-kB activation and
upregulation of a subset of psoriasis-associated genes in keratinocytes. These genes
included chemokine (C-C motif) ligand 20 (CCL20) and IL-8. CARD14 is localized
mainly in the basal and suprabasal layers of healthy skin epidermis, whereas in
lesional psoriatic skin, it is reduced in the basal layer and more diffusely upregulated
in the suprabasal layers of the epidermis. The authors propose that, after a triggering
event that can include epidermal injury, rare gain-of-function mutations in CARD14
initiate a process that includes infl ammatory cell recruitment by keratinocytes. This
perpetuates a vicious cycle of epidermal infl ammation and regeneration, a cycle
which is the hallmark of psoriasis. The identifi cation of the gene and its associated
pathways/proteins open an avenue of therapeutic targets for drug development in
psoriasis with the hope that a more specifi c and effective therapy can be developed.
Biomarkers of Lysosomal Storage Disorders
Although several therapies are available or in development for lysosomal storage
disorders (LSDs), assessment of therapeutic effi cacy is limited by the lack of bio-
markers to assess disease progression and severity. This is particularly true for rare
diseases such as LSDs, since natural history data from human populations are often
lacking. Gene expression analysis in the acid sphingomyelinase-defi cient mouse
model (ASMKO) of Types A and B Niemann-Pick disease (NPD) has been used to
identify novel serum biomarkers (Dhami et al. 2006 ). Microarray and real-time
PCR analyses were used to compare mRNA expression in ASMKO and normal
mice in two important sites of pathology, lung and brain, and from these data identi-
fi ed and validated several potential biomarkers. The cytokine MIP-1α was markedly
elevated in ASMKO mouse serum, and following enzyme replacement therapy
(ERT) it was reduced to normal levels. Total iron levels were similarly elevated in
ASMKO mice, refl ective of the elevated ferritin light chain transcript, and decreased
to normal after ERT. Serum growth hormone levels were also elevated in ASMKO
mice and were reduced to normal after brain-directed gene therapy, but not
ERT. These studies illustrate the value of gene expression analysis for the identifi ca-
tion of biomarkers, and provide new insight into the pathobiology of NPD.
The mucopolysaccharidoses (MPS) is another group of LSDs presenting with
broad multi-system disease and a continuous range of phenotypes. Currently, there
are no objective biomarkers of MPS disease that clearly refl ect disease severity or
therapeutic responsiveness. Formation of the heparin cofactor II-thrombin (HCII-T)
complex, a well-known serine protease inhibitor (serpin)-serine protease complex,
has been identifi ed as an informative biomarker for MPS I by using proteomic stud-
ies in the murine MPS I model. HCII-T complex was also elevated in plasma from
MPS I patients. The degree of HCII-T complex formation appears to correlate with
Biomarkers for Genetic Disorders