Ping Tu

Exome sequencing reveals mutations in TRPV3 as a cause of Olmsted syndrome.

Olmsted syndrome (OS) is a rare congenital disorder characterized by palmoplantar and periorificial keratoderma, alopecia in most cases, and severe itching. The genetic basis for OS remained unidentified. Using whole-exome sequencing of case-parents trios, we have identified a de novo missense mutation in TRPV3 that produces p.Gly573Ser in an individual with OS. Nucleotide sequencing of five additional affected individuals also revealed missense mutations in TRPV3 (which produced p.Gly573Ser in three cases and p.Gly573Cys and p.Trp692Gly in one case each). Encoding a transient receptor potential vanilloid-3 cation channel, TRPV3 is primarily expressed in the skin, hair follicles, brain, and spinal cord. In transfected HEK293 cells expressing TRPV3 mutants, much larger inward currents were recorded, probably because of the constitutive opening of the mutants. These gain-of-function mutations might lead to elevated apoptosis of keratinocytes and consequent skin hyperkeratosis in the affected individuals. Our findings suggest that TRPV3 plays essential roles in skin keratinization, hair growth, and possibly itching sensation in humans and selectively targeting TRPV3 could provide therapeutic potential for keratinization or itching-related skin disorders.

Deficiency of SATB1 expression in Sézary cells causes apoptosis resistance by regulating FasL/CD95L transcription

Sézary syndrome (SS) is an aggressive subtype of cutaneous T-cell lymphoma that is characterized by circulating leukemic Sézary cells. The accumulation of these malignant cells has been shown to be the result of the resistance to apoptosis, in particular, activation-induced cell death. However, the mechanism of apoptosis resistance remains unknown. By characterizing the gene transcription profiles of purified CD4(+)CD7(-) Sézary cells from patients with SS and cultured Sézary cells, it was found that Sézary cells are deficient in the expression of special AT-rich region binding protein 1 (SATB1), a key regulator of T-cell development and maturation. Retrovirus-mediated gene transduction revealed that SATB1 restoration in cultured Sézary cells (Hut78) triggered spontaneous cell death and sensitized Hut78 cells to activation-induced cell death, with associated activation of caspase 8 and caspase 3. Furthermore, endogenous expression of FasL in Sézary cells was increased in transcriptional and translational levels on restoration of SATB1 expression in cultured Sézary cells. These results suggest that deficiency in SATB1 expression in Sézary cells plays an important role in SS pathogenesis by causing apoptosis resistance. Thus, restoration of SATB1 expression may represent a potential molecular targeted therapy for SS, which does not have a cure at present.

SATB1 overexpression promotes malignant T-cell proliferation in cutaneous CD30+ lymphoproliferative disease by repressing p21.

Cutaneous CD30(+) lymphoproliferative disease (CD30(+)LPD), characterized by the presence of CD30(+) anaplastic large T cells, comprises the second most common group of cutaneous T-cell lymphoma (CTCL). However, little is known about the pathobiology of the CD30(+) lymphoma cells, as well as the mechanisms of disease progression. Here we report that Special AT-rich region binding protein 1 (SATB1), a thymocyte specific chromatin organizer, is over-expressed in CD30(+) lymphoma cells in most CD30(+)LPDs, and its expression is upregulated during disease progression. Our findings show that SATB1 silencing in CD30(+)LPD cells leads to G1 cell cycle arrest mediated by p21 activation. Using chromatin immunoprecipitation, luciferase assays, and mutational analysis, we demonstrate that SATB1 directly regulates the transcription of p21 in a p53-independent manner. Moreover, DNA demethylation on a specific CpG-rich region of the SATB1 promoter is associated with the upregulation of SATB1 during disease progression. These experiments define a novel SATB1-p21 pathway in malignant CD30(+) T lymphocytes, which provides novel molecular insights into the pathogenesis of CD30(+)LPDs and possibly leads to new therapies.

New mutations in the transglutaminase 1 gene in three families with lamellar ichthyosis

Background.  Autosomal recessive lamellar ichthyosis (LI) is a severe skin disorder characterized by generalized hyperkeratosis. Gene mutation in transglutaminase 1 (TGM1), which mediates cross‐links in the formation of the cell envelope during terminal differentiation of epidermis, has been identified as a cause of LI.

Primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma clinically simulating pyoderma gangrenosum

Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma is a rare, recently recognized disease. We report a case presenting with a clinical resemblance to pyoderma gangrenosum (PG), and a particularly aggressive clinical course. A 19-year-old Chinese woman presented with a 1-year history of painful papular lesions on the shoulders and back, which rapidly became necrotic, progressed to enlarging ulcers and spread to involve the face, limbs and breasts. She also had an intermittent fever. Some old lesions resolved but new lesions continued to develop, with extensive ulceration and pain. Despite treatment with prednisone, the lesions continued to increase in number and size. The patient had previously been healthy. On examination, disseminated well-circumscribed ulcers, measuring 10–100 mm in diameter, some of which were deep with a purulent base and dusky-red, raised, and undermined borders, were seen on the breasts and extensor surface of limbs, along with multiple violaceous papules (Fig. 1). Histopathological examination revealed focal epidermotropism and nodular infiltration of medium to large, pleomorphic lymphoid cells in the dermis and the upper portion of the subcutaneous fat. Angiocentric infiltration was prominent, but there was no angiodestruction. Rimming of fat cells by the atypical infiltrate was not evident. Furthermore, a small number of eosinophils were also present. Immunostaining performed on paraffin wax-embedded sections showed that most of the atypical lymphocytes expressed CD3, CD8, CD43, T-cell receptor-b, and T-cell intracellular antigen 1, and were negative for CD4, CD45RO, CD20, CD30, CD5, CD56 and granzyme B. (Fig. 2a–d) In addition, some atypical cells (50%) were positive for Ki-67 (Fig. 2e). In situ hybridization for the detection of Epstein–Barr virus-encoded RNAs (EBERs) was negative. Routine laboratory studies were unremarkable. No atypical lymphocytes were found in the peripheral blood. Examination of a bone-marrow biopsy revealed involvement by T-cell lymphoma. Computed tomography revealed no lymphadenopathy or any visceral involvement. Analysis of the T-cell receptor c gene using PCR found clonal rearrangement. Based on these findings, a diagnosis of primary cutaneous epidermotropic CD8+ cytotoxic T-cell lymphoma was

DNA‐based prenatal diagnosis in a Chinese family with xeroderma pigmentosum group A

Background  Xeroderma pigmentosum (XP) is a group of autosomal recessive diseases characterized by hypersensitivity to ultraviolet rays. Among its eight complementation groups, XP group A (XPA) is the most severe type. The XPAC gene has been identified as the defective gene in XPA patients.

Preliminary exploration of the clinical features of Chinese patients with skin malignancies and premalignancies: a retrospective study of 1420 cases from Peking University First Hospital

Background  The epidemiological and clinical characterization data of skin malignancies and premalignancies in Chinese population is scarce and inadequate.

Unique features of PTCH1 mutation spectrum in Chinese sporadic basal cell carcinoma

Background  Alterations of the PTCH1 gene have been found to contribute to both familial and sporadic basal cell carcinoma (BCC), especially in Caucasian patients. Furthermore, the majority of PTCH1 gene mutations in sporadic BCCs in Caucasian patients carry ultraviolet (UV) signatures, suggesting the key role of UV light in BCC development. However, sporadic BCC in non‐Caucasian population has a lower incidence, and the pathogenesis remains largely unknown. To date, there has been no mutation analysis on PTCH1 gene in Chinese patients with sporadic BCCs.

SPINK5 gene mutation and decreased LEKTI activity in three Chinese patients with Netherton's syndrome

Nethertons syndrome is a rare autosomal recessive disorder caused by mutations of the SPINK5 gene, which encodes the lymphoepithelial Kazal‐type‐related inhibitor (LEKTI) protein. We observed microstructural changes and detected LEKTI activity and SPINK5 gene mutation in three Chinese patients with Nethertons syndrome. Decreased LEKTI activity was found in the skin of patients. Lamellar bodies and foci of electron‐dense material were detected in the intercellular spaces of the stratum corneum. A novel homozygous splicing mutation of 1430 + 2 T→G was found in the SPINK5 gene in one proband. No mutation was found in the other family.

BCL11B-Mediated Epigenetic Repression Is a Crucial Target for Histone Deacetylase Inhibitors in Cutaneous T-Cell Lymphoma

The treatment options for advanced cutaneous T-cell lymphoma (CTCL) are limited because of its unclear pathogenesis. Histone deacetylase (HDAC) inhibitors (HDACis) are recently developed therapeutics approved for refractory CTCL. However, the response rate is relatively low and unpredictable. Previously, we discovered that BCL11B, a key T-cell development regulator, was aberrantly overexpressed in mycosis fungoides, the most common CTCL, as compared with benign inflammatory skin. In this study, we identified a positive correlation between BCL11B expression and sensitivity to HDACi in CTCL lines. BCL11B suppression in BCL11B-high cells induced cell apoptosis by de-repressing apoptotic pathways and showed synergistic effects with suberoylanilide hydroxamic acid (SAHA), a pan-HDACi. Next, we identified the physical interaction and shared downstream genes between BCL11B and HDAC1/2 in CTCL lines. This interaction was essential in the anti-apoptosis effect of BCL11B, and the synergism between BCL11B suppression and HDACi treatment. Further, in clinical samples from 46 mycosis fungoides patients, BCL11B showed increased but varied expression in advanced tumor stage. Analysis of four patients receiving SAHA treatment suggested a positive correlation between BCL11B expression and favorable response to SAHA treatment. In conclusion, BCL11B may serve as a therapeutic target and a useful marker for improving HDACi efficacy in advanced CTCL.