Dingfang Bu

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.

Autoantibody production from a thymoma and a follicular dendritic cell sarcoma associated with paraneoplastic pemphigus.

Background  Paraneoplastic pemphigus (PNP) is an autoimmune mucocutaneous disease. We previously reported that B cells in a Castleman tumour associated with PNP produced autoantibodies. However, it is uncertain whether the production of autoantibodies from the associated tumour is a common mechanism in PNP.

A novel splice site mutation in collagen type VII gene in a Chinese family with dominant dystrophic epidermolysis bullosa pruriginosa.

Dystrophic epidermolysis bullosa pruriginosa, a subtype of epidermolysis bullosa dystrophica and a heterogeneous inherited disease, is characterized by pruritus, excoriated nodular prurigo-like lesions, skin fragility, altered anchoring fibrils and loss of dermal-epidermal adhesion. Mutation in type VII collagen gene (COL7A1) is thought to be implicated in the underlying change for dystrophic epidermolysis bullosa pruriginosa. We report here a large family of dominant dystrophic epidermolysis bullosa pruriginosa. Mutation analysis using polymerase chain reaction and direct sequencing demonstrated a novel nucleotide substitution of 6899A-->G in exon 87 in one COL7A1 allele of the proband and 18 affected family members. This substitution was not found in 100 normal alleles. Polymerase chain reaction and sequencing of the cDNA, reverse transcribed from the probands peripheral lymphocyte RNA, suggest that this mutation causes aberrant COL7A1 mRNA splicing of exon 87 skipping. Clinical features and pedigree analysis suggest that 6899A-->G substitution is a mutation with full penetrance and variable expressivity.

Genotyping of HLA-I and HLA-II alleles in Chinese patients with paraneoplastic pemphigus.

Background  Class I and class II HLA genes are thought to play a role in the immunopathogenesis of bullous dermatoses such as pemphigus vulgaris and pemphigus foliaceus, but we know little about the genetic background of paraneoplastic pemphigus (PNP) in Chinese patients.

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.

A novel missense mutation in the SLC6A19 gene in a Chinese family with Hartnup disorder

Background  Hartnup disease is a rare autosomal‐recessive abnormality of renal and gastrointestinal neutral amino acid transport associated with neurologic, psychiatric, and dermatologic symptoms. Mutations in the SLC6A19 gene have been proposed to be responsible for the underlying changes in this disorder.

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.

Immunoglobulin variable region gene analysis to the autoantibody-secreting B cells from tumors in association with paraneoplastic autoimmune multiorgan syndrome.

Objectives  We have studied the role of lymphoproliferative tumors in the pathogenesis of autoimmune and the origin of the autoantibodies in PNP. Objectives of this study is to understand the characteristics of immunoglobulin genes of the B‐cells isolated from the tumor which can produce auto‐antibody.

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.