Masayo Nomura

A SNP in the ABCC11 gene is the determinant of human earwax type

Human earwax consists of wet and dry types. Dry earwax is frequent in East Asians, whereas wet earwax is common in other populations. Here we show that a SNP, 538G → A (rs17822931), in the ABCC11 gene is responsible for determination of earwax type. The AA genotype corresponds to dry earwax, and GA and GG to wet type. A 27-bp deletion in ABCC11 exon 29 was also found in a few individuals of Asian ancestry. A functional assay demonstrated that cells with allele A show a lower excretory activity for cGMP than those with allele G. The allele A frequency shows a north-south and east-west downward geographical gradient; worldwide, it is highest in Chinese and Koreans, and a common dry-type haplotype is retained among various ethnic populations. These suggest that the allele A arose in northeast Asia and thereafter spread through the world. The 538G → A SNP is the first example of DNA polymorphism determining a visible genetic trait.

Mutations in UVSSA cause UV-sensitive syndrome and impair RNA polymerase IIo processing in transcription-coupled nucleotide-excision repair

UV-sensitive syndrome (UVSS) is a genodermatosis characterized by cutaneous photosensitivity without skin carcinoma. Despite mild clinical features, cells from individuals with UVSS, like Cockayne syndrome cells, are very UV sensitive and are deficient in transcription-coupled nucleotide-excision repair (TC-NER), which removes DNA damage in actively transcribed genes. Three of the seven known UVSS cases carry mutations in the Cockayne syndrome genes ERCC8 or ERCC6 (also known as CSA and CSB, respectively). The remaining four individuals with UVSS, one of whom is described for the first time here, formed a separate UVSS-A complementation group; however, the responsible gene was unknown. Using exome sequencing, we determine that mutations in the UVSSA gene (formerly known as KIAA1530) cause UVSS-A. The UVSSA protein interacts with TC-NER machinery and stabilizes the ERCC6 complex; it also facilitates ubiquitination of RNA polymerase IIo stalled at DNA damage sites. Our findings provide mechanistic insights into the processing of stalled RNA polymerase and explain the different clinical features across these TC-NER–deficient disorders.

BAC array CGH reveals genomic aberrations in idiopathic mental retardation

Array using 2,173 BAC clones covering the whole human genome has been constructed. All clones spotted were confirmed to show a unique signal at the predicted chromosomal location by FISH analysis in our laboratory. A total of 30 individuals with idiopathic mental retardation (MR) were analyzed by comparative genomic hybridization using this array. Three deletions, one duplication, and one unbalanced translocation could be detected in five patients, which are likely to contribute to MR. The constructed array was shown to be an efficient tool for the detection of pathogenic genomic rearrangements in MR patients as well as copy number polymorphisms (CPNs).

Paroxysmal kinesigenic choreoathetosis (PKC): confirmation of linkage to 16p11-q21, but unsuccessful detection of mutations among 157 genes at the PKC-critical region in seven PKC families

AbstractParoxysmal kinesigenic choreoathetosis (PKC) is a paroxysmal movement disorder of unknown cause. Although the PKC-critical region (PKCCR) has been assigned to the pericentromeric region of chromosome 16 by several studies of families from various ethnic backgrounds, the causative gene has not yet been identified. In the present study, we performed linkage and haplotype analysis in four new families with PKC, as well as an intensive polymerase chain reaction (PCR) based mutation analysis in seven families for a total of 1,563 exons from 157 genes mapped around the PKCCR. Consequently, the linkage/haplotype analysis revealed that PKC was assigned to a 24-cM segment between D16S3131 and D16S408, the result confirming the previously defined PKCCR, but being unable to narrow it down. Although the mutation analysis of the 157 genes was unsuccessful at identifying any mutations that were shared by patients from the seven families, two nonsynonymous substitutions, i.e., 6186C>A in exon 3 of SCNN1G and 45842A>G in exon 29 of ITGAL, which were segregated with the disease in Families C and F, respectively, were not observed in more than 400 normal controls. Thus, one of the two genes, SCNN1G and ITGAL, could be causative for PKC, but we were not able to find any other mutations that explain the PKC phenotype.

No detectable genomic aberrations by BAC array CGH in Kabuki make-up syndrome patients.

Noriko Miyake, Osamu Shimokawa, Naoki Harada, Nadia Sosonkina, Aiko Okubo, Hiroki Kawara, Nobuhiko Okamoto, Hirofumi Ohashi, Kenji Kurosawa, Kenji Naritomi, Tadashi Kaname, Toshiro Nagai, Vorasuk Shotelersuk, Jia-Woei Hou, Yoshimitsu Fukushima, Tatsuro Kondoh, Tadashi Matsumoto, Toshihiko Shinoki, Mitsuhiro Kato, Hidefumi Tonoki, Masayo Nomura, Ko-ichiro Yoshiura, Tatsuya Kishino, Tohru Ohta, Norio Niikawa, and Naomichi Matsumoto * Department of Human Genetics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan Department of Pediatrics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan CREST, Japan Science and Technology Agency, Kawaguchi, Japan Kyushu Medical Science Nagasaki Laboratory, Nagasaki, Japan Department of Planning and Research, Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Japan Division of Medical Genetics, Saitama Children’s Medical Center, Iwatsuki, Japan Division of Medical Genetics, Kanagawa Children’s Medical Center, Yokohama, Japan Department of Medical Genetics, University of the Ryukyus School of Medicine, Nishihara, Japan Department of Pediatrics, Koshigaya Hospital, Dokkyo University School of Medicine, Koshigaya, Japan Department of Pediatrics, Faculty of Medicine, Chulalongkorn University and Hospital, Bangkok, Thailand Department of Pediatrics, Division of Medical Genetics/Metabolism, Chang Gung Children’s Hospital, Taoyuan, Taiwan Department of Medical Genetics, Shinshu University School of Medicine, Matsumoto, Japan Department of Nursing, Nagasaki University School of Health Sciences, Nagasaki, Japan Department of Pediatrics, Mie University School of Medicine, Tsu, Japan Department of Pediatrics, Yamagata University School of Medicine, Yamagata, Japan Department of Pediatrics, Hokkaido University School of Medicine, Sapporo, Japan Division of Functional Genomics, Center for Frontier Life Sciences, Nagasaki University, Nagasaki, Japan The Research Institute of Personalized Health Sciences, Health Sciences University of Hokkaido, Ishikari-tobetsu, Japan Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan

Eosinophil infiltration in three patients with generalized atrophic benign epidermolysis bullosa from a Japanese family: molecular genetic and immunohistochemical studies

AbstractGeneralized atrophic benign epidermolysis bullosa (GABEB), a subtype of epidermolysis bullosa (EB), is an autosomal recessive skin disease characterized by derm-epidermal separation leading to skin fragility and atrophy and other associated abnormalities. Although a few reports demonstrated that eosinophils are infiltrating beneath bullas in infants with some types of EB, no such condition in adult GABEB patients has been known. Here we report on three adult patients with GABEB from a Japanese family, whose bullous skin lesions showed massive eosinophil infiltration. One of the three patients showed amyloid deposition at the intestine, kidney, and skin. Linkage analysis revealed that GABEB in the family was linked to COL17A1 with a maximum LOD score of 3.08. Mutation analysis identified in the three patients a homozygous insertional mutation, 209-210insCA, in exon 5 of COL17A1. The expression of mutated COL17A1 was confirmed by semiquantitative RT-PCR, but no signals for truncated COL17A1 protein were detected by the immunohistochemical studies using antibodies against BP180. Furthermore, no autoantibody against the mutant protein was detected by western blot analysis. It is thus less likely that autoantibody and/or a local immune reaction in their skin has a primary role in eosinophil infiltration in these patients.