The novel functional link between LEKTI and TG1 should be taken into account when considering the development of a targeted topical protein therapy for Netherton syndrome.
Netherton syndrome (NS) is a rare but severe type of ichthyosis characterized by atopy, allergies, and potentially lethal skin overdesquamation associated with highly elevated proteolytic activities in LEKTI-deficient epidermis.
LEKTI is known to be an essential molecule for the epidermal skin barrier, as demonstrated by SPINK5 nonsense mutation, which results in Netherton syndrome.
The identification of SPINK5, which encodes for the serine protease inhibitor LEKTI, as the gene responsible for Netherton syndrome, enabled the search for causative mutations in Netherton syndrome patients and families.
KLK5 was proposed as a major protease in NS pathology, however its inactivation is not sufficient to rescue the lethal phenotype of LEKTI-deficient mice.
However, LEKTI immunohistochemistry remains the essential diagnostic investigation in cases with misleading or nonspecific histological features and is mandatory for the definitive diagnosis of NS in all patients.
Netherton syndrome (NS) is a rare autosomal recessive disorder which is caused by mutations in the SPINK5 gene encoding the serine-protease inhibitor LEKTI.
SPINK5 knockdown in organotypic human skin culture as a model system for Netherton syndrome: effect of genetic inhibition of serine proteases kallikrein 5 and kallikrein 7.
It is proposed that a lack of inhibition of proteases due to a deficiency of LEKTI in the pituitary gland leads to the overprocessing of human GH in NS.
In vitro and in vivo studies in murine models and in NS patients have cast light on the pathogenesis of the disease and shown that LEKTI deficiency results in unopposed kallikrein-related peptidase 5 (KLK5) and KLK7 activities and to the overactivity of a new epidermal protease, elastase 2 (ELA2).
A SIN-lentiviral vector encoding the codon-optimized SPINK5 gene under the control of a 572 bp element derived from the human involucrin promoter can confer compartment-specific LEKTI expression in NS keratinocytes with restoration of normal skin architecture.
Clinical expression and new SPINK5 splicing defects in Netherton syndrome: unmasking a frequent founder synonymous mutation and unconventional intronic mutations.
Clinical expression and new SPINK5 splicing defects in Netherton syndrome: unmasking a frequent founder synonymous mutation and unconventional intronic mutations.
Loss-of-function mutations in the LEKTI encoding gene SPINK5 cause Netherton syndrome, a rare and severe genetic skin disease with a profound skin barrier defect and atopic manifestations.