title: Novel splice site mutation in the fumarate hydratase (FH) gene is associated with multiple cutaneous leiomyomas in a Japanese patient.
abstract: Cutaneous leiomyoma is a benign skin tumor that originates from the smooth muscle, such as the arrector pili muscle of the hair follicles. Familial cases with multiple cutaneous leiomyomas exist, which typically show an autosomal dominant inheritance trait. Most patients with the disease are known to carry heterozygous germ line mutations in the fumarate hydratase (FH) gene and can be complicated by tumors in internal organs, especially uterine leiomyoma and renal cell cancer in high frequency. In this study, we identified a Japanese male patient with multiple cutaneous leiomyomas and found a novel heterozygous splice site mutation, c.738 + 2T>A, in the FH gene of the patient, which was unexpectedly inherited from his unaffected father. Further analysis demonstrated loss of heterozygosity in the tumor tissue, which resulted in a hemizygote state of the mutant allele. Expression studies with the tumor tissue showed that the mutation led to skipping of exon 5 at mRNA levels, which was predicted to cause an in-frame deletion of FH protein (p.Ser186_Gln246del). The protein structure analysis strongly suggested that the deletion would severely disrupt the conformation of the FH protein including the substrate-binding domain, and thus would severely affect the expression and the function. Our findings further disclose the molecular basis of multiple cutaneous leiomyomas and also provide precious information to the mutation carriers in the family for an early diagnosis of renal cell cancer in the future.
authors.affiliation: Division of Dermatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Yukina
authors.initials: Y
authors.lastname: Yoshinaga
authors.affiliation: Faculty of Agriculture, Niigata University, Niigata, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nakai
authors.affiliation: Division of Dermatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Ryota
authors.initials: R
authors.lastname: Hayashi
authors.affiliation: Division of Dermatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Ito
authors.affiliation: Division of Dermatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kariya
authors.affiliation: Division of Dermatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Ito
authors.affiliation: Division of Dermatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.|Laboratory of Genetic Skin Diseases, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Shimomura
mesh_terms: D005649:Fumarate Hydratase / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D018231:Leiomyomatosis / Q000201:enzymology* / Q000235:genetics*; D019656:Loss of Heterozygosity; D008297:Male; D008958:Models, Molecular; D009154:Mutation; D011487:Protein Conformation; D022821:RNA Splice Sites; D012878:Skin Neoplasms / Q000201:enzymology* / Q000235:genetics*; D055815:Young Adult
chemical_list: D022821:RNA Splice Sites; D005649:Fumarate Hydratase
keywords: cutaneous leiomyoma; exon skipping; fumarate hydratase; splice site mutation