Trichohyalin (TCHH) is a structural protein responsible for the proper cylindrical fiber topology of the hair shaft. TCHH binds other TCHH and keratin-intermediate filaments creating the proper cross-links and cylindrical shape of the hair shaft. PADI3 and TGM3 are two enzymes responsible for post-translational modification of TCHH important for cross-linking of TCHH within the hair. In Uncombable Hair Syndrome mutations in TCHH, PADI3, or TGM3 result in improper cross-linking and the resulting irregular shape of the hair shaft.The particular defect in TCHH as a structural component of hair may be a defect of deimination. Deimination converts the amino acid arginine to the amino acid citrulline. This conversion is done by calcium-dependent enzymes known as peptidylarginine deiminases (PADs). PADI3 is a member of this enzyme class. One study reported PAD involvement in skin and skin-related diseases, particularly at the hair follicle. Alterations to PAD activity resulted in the development of Uncombable Hair Syndrome. Another study examined the transglutaminase (TG) family of enzymes and their involvement in UHS. This family of enzymes includes TGM3, which is expressed in epidermal cells. Mutations in TGM3 may therefore reduce or alter the intermolecular cross-linking important for hair shaft formation, leading to Uncombable Hair Syndrome.Another molecular mechanism of UHS was proposed by Ralph Trueb in 2003. He suggested that premature keratinization of the inner hair root forms a rigid sheath that alters the shape of a hair strand as it grows out of the root.
Uncombable Hair Syndrome 1
Uncombable Hair Syndrome 1 is caused by a defect in the Trichohyalin gene (TCHH) found in hair follicles and some parts of hair strands. It serves as a scaffold protein, with involucrin, in cell envelope organization. The trichohyalin gene is produced and changed by other proteins and to molecules such as keratin intermediate filaments to form organized cross-links. These networks provide the hair shaft with its cylindrical form. This, in turn, leads to frizzy hair, resulting in uncombable hair. The chromosomal location for this TCHH gene is located on chromosome 1. The condition usually improves over time, and will have better hair structure once it reaches adolescence.It is still being decided whether TCHH is autosomal dominant, or autosomal recessive. In an experiment, they identified the causative mutations of UHS in 3 genes; PADI3, TGM3, and TCHH in 11 children. These children carried homozygous/heterozygous mutations in those 3 genes, which resulted in autosomal recessive inheritance. Because it was identified as autosomal recessive inheritance, scanning electron microscopy was performed in order to rule out autosomal dominance since this type of gene can also be autosomal dominant to a certain extent. Uncombable Hair Syndrome 2
Uncombable Hair Syndrome 2 is caused by a defect in Transglutaminase 3 (TGM3) gene. This gene helps provide instructions for creating an enzyme known as Transglutaminase 3. This gene is found in skin cells known as keratinocytes and corneocytes. This helps frame the scalp, root, and strands of hair. It helps the molecules bind 
proteins.