DSG4

At least 10 mutations in the DSG4 gene have been found to cause autosomal recessive hypotrichosis, a condition that results in sparse hair growth (hypotrichosis) on the scalp, and less frequently, other parts of the body. A particular mutation that deletes a piece of genetic material in the DSG4 gene (written as Ex5_8) is a common cause of the condition in individuals of Pakistani ancestry. This mutation impairs the protein's ability to help cells attach to one another. Other DSG4 gene mutations result in the production of abnormal DSG4 proteins that cannot communicate signals between cells within hair follicles or skin. As a result, hair follicles are structurally abnormal and often underdeveloped. Irregular hair follicles alter the structure and growth of hair shafts, leading to fragile hair that breaks easily. A lack of normal DSG4 protein function may weaken the skin and contribute to the skin problems sometimes seen in individuals with autosomal recessive hypotrichosis.

Mutations in the DSG4 gene have been found in people with monilethrix, a hair condition characterized by strands of hair with a beaded appearance. The hair is also short, brittle and breaks easily. The mutations associated with this condition can affect any part of the DSG4 protein, but these changes typically alter the extracellular domain, which is the region of the protein outside the cell that interacts with other cells. In people with monilethrix, the cortex of the affected hair shaft appears abnormal. However, it is unclear how mutations in the DSG4 gene are related to the abnormality in the cortex or the beaded appearance of the hair.

It is unknown why some individuals with DSG4 gene mutations develop monilethrix and others develop autosomal recessive hypotrichosis (described above). These conditions may represent different forms of the same disorder.