title: Novel mutations of the transglutaminase 1 gene in lamellar ichthyosis.
abstract: Lamellar ichthyosis, one form of congenital autosomal recessive ichthyosis, is caused by mutations in the gene (TGM1) encoding the transglutaminase 1 enzyme. Mutations, deletions, or insertion of TGM1 have been reported so far. Here we report that three novel mutations of TGM1, D101V, N288T, and R306W, cause lamellar ichthyosis in two different families. The patient in family LI-KD has N288T and R306W mutations, and the patient in family LI-LK has D101V and R306W mutations. The activity of the transglutaminase 1 enzyme of the patient in family LI-LK was only about 15% of normal. Also, three-dimensional structural prediction analyses revealed that the N288T and R306W mutations, and possibly the D101V mutation, cause misfolding in the central catalytic core domain of the transglutaminase 1 enzyme that would probably result in reduced enzyme activity. Our data suggest that the greatly reduced transglutaminase 1 activities are due to disruptions of the native folding of transglutaminase 1, and that these mutations may play a critical role in the pathology of lamellar ichthyosis.
authors.affiliation: Department of Dermatology, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Republic of Korea. jmyang@smc.samsung.co.kr
authors.forename: J M
authors.initials: JM
authors.lastname: Yang
authors.forename: K S
authors.initials: KS
authors.lastname: Ahn
authors.forename: M O
authors.initials: MO
authors.lastname: Cho
authors.forename: K
authors.initials: K
authors.lastname: Yoneda
authors.forename: C H
authors.initials: CH
authors.lastname: Lee
authors.forename: J H
authors.initials: JH
authors.lastname: Lee
authors.forename: E S
authors.initials: ES
authors.lastname: Lee
authors.forename: E
authors.initials: E
authors.lastname: Candi
authors.forename: G
authors.initials: G
authors.lastname: Melino
authors.forename: B
authors.initials: B
authors.lastname: Ahvazi
authors.forename: P M
authors.initials: PM
authors.lastname: Steinert
mesh_terms: D019943:Amino Acid Substitution; D002478:Cells, Cultured; D005091:Exons; D005260:Female; D006801:Humans; D006860:Hydrogen Bonding; D017490:Ichthyosis, Lamellar / Q000235:genetics*; D007231:Infant, Newborn; D015603:Keratinocytes / Q000166:cytology / Q000201:enzymology; D020125:Mutation, Missense; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000032:analysis; D012867:Skin / Q000166:cytology; D013329:Structure-Activity Relationship; D011503:Transglutaminases / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D011503:Transglutaminases; C105804:transglutaminase 1