Cystatin M/E Variant Causes Autosomal Dominant Keratosis Follicularis Spinulosa Decalvans by Dysregulating Cathepsins L and V

Keratosis follicularis spinulosa decalvans (KFSD) is a rare cornification disorder with an X-linked recessive inheritance in most cases. Pathogenic variants causing X-linked KFSD have been described in MBTPS2, the gene for a membrane-bound zinc metalloprotease that is involved in the cleavage of sterol regulatory element binding proteins important for the control of transcription. Few families have been identified with an autosomal dominant inheritance of KFSD. We present two members of an Austrian family with a phenotype of KFSD, a mother and her son. The disease was not observed in her parents, pointing to a dominant inheritance with a de novo mutation in the index patient. Using whole-exome sequencing, we identified a heterozygous missense variant in CST6 in DNA samples from the index patient and her affected son. In line with family history, the variant was not present in samples from her parents. CST6 codes for cystatin M/E, a cysteine protease inhibitor. Patient keratinocytes showed increased expression of cathepsin genes CTSL and CTSV and reduced expression of transglutaminase genes TGM1 and TGM3. A relative gain of active, cleaved transglutaminases was found in patient keratinocytes compared to control cells. The variant found in CST6 is expected to affect protein targeting and results in marked disruption of the balance between cystatin M/E activity and its target proteases and eventually transglutaminases 1 and 3. This disturbance leads to an impairment of terminal epidermal differentiation and proper hair shaft formation seen in KFSD.

Cystatin M/E (Cystatin 6): A Janus-Faced Cysteine Protease Inhibitor with Both Tumor-Suppressing and Tumor-Promoting Functions

Alongside its contribution in maintaining skin homeostasis and its probable involvement in fetal and placental development, cystatin M/E (also known as cystatin 6) was first described as a tumor suppressor of breast cancer. This review aims to provide an update on cystatin M/E with particular attention paid to its role during tumorigenesis. Cystatin M/E, which is related to type 2 cystatins, displays the unique property of being a dual tight-binding inhibitor of both legumain (also known as asparagine endopeptidase) and cysteine cathepsins L, V and B, while its expression level is epigenetically regulated via the methylation of the CST6 promoter region. The tumor-suppressing role of cystatin M/E was further reported in melanoma, cervical, brain, prostate, gastric and renal cancers, and cystatin M/E was proposed as a biomarker of prognostic significance. Contrariwise, cystatin M/E could have an antagonistic function, acting as a tumor promoter (e.g., oral, pancreatic cancer, thyroid and hepatocellular carcinoma). Taking into account these apparently divergent functions, there is an urgent need to decipher the molecular and cellular regulatory mechanisms of the expression and activity of cystatin M/E associated with the safeguarding homeostasis of the proteolytic balance as well as its imbalance in cancer.

FABP1 and FABP3 Have High Predictive Values for Renal Replacement Therapy in Patients with Acute Kidney Injury

Background/Aims: Early initiation of renal replacement therapy (RRT) is recommended in order to improve the clinical outcome of patients who develop an acute kidney injury (AKI). However, markers that guide an early RRT initiation do not really exist currently. Methods: Urine and serum samples were prospectively collected from 120 AKI patients. Depending on the necessity of initiating RRT, patients were divided into 2 different groups: dialysis (n = 52) and non-dialysis (n = 68). Results: Comparative urinary proteomic analyses identified 4 different proteins (fatty acid binding proteins 1 and 3 (FABP1 and FABP3), β-2-microglobulin (B2M), cystatin-M (CST6)) that discriminate AKI patients with high risk for RRT. Western blot analysis confirmed the proteomics data for FABP1 and FABP3 but not for B2M and CST6. Validation analysis confirmed that the FABP1 and FABP3 fulfilled the requirement of functioning as markers for AKI patients with risk to dialysis (p < 0.001). Conclusion: The release of high amounts of FABP1 and FABP3 in urine of AKI patients could serve as a diagnostic/prognosis marker for RRT initiation in these patients.