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Yoko Narumi,
Yoko Aoki,
Tetsuya Niihori,
Giovanni Neri,
Hélène Cavé,
Alain Verloes,
Caroline Nava,
Maria Ines Kavamura,
Nobuhiko Okamoto,
Kenji Kurosawa, [......],
Pablo Lapunzina,
Hirofumi Ohashi,
Yoshio Makita,
Ikuko Kondo,
Shigeru Tsuchiya,
Etsuro Ito,
Kiyoko Sameshima, Kumi Kato,
Shigeo Kure,
Yoichi Matsubara
[show abstract]
[hide abstract]
ABSTRACT: Cardio-facio-cutaneous (CFC) syndrome is a multiple congenital anomaly/mental retardation syndrome characterized by heart defects, a distinctive facial appearance, ectodermal abnormalities and mental retardation. Clinically, it overlaps with both Noonan syndrome and Costello syndrome, which are caused by mutations in two genes, PTPN11 and HRAS, respectively. Recently, we identified mutations in KRAS and BRAF in 19 of 43 individuals with CFC syndrome, suggesting that dysregulation of the RAS/RAF/MEK/ERK pathway is a molecular basis for CFC syndrome. The purpose of this study was to perform comprehensive mutation analysis in 56 patients with CFC syndrome and to investigate genotype-phenotype correlation. We analyzed KRAS, BRAF, and MAP2K1/2 (MEK1/2) in 13 new CFC patients and identified five BRAF and one MAP2K1 mutations in nine patients. We detected one MAP2K1 mutation in three patients and four new MAP2K2 mutations in four patients out of 24 patients without KRAS or BRAF mutations in the previous study [Niihori et al., 2006]. No mutations were identified in MAPK3/1 (ERK1/2) in 21 patients without any mutations. In total, 35 of 56 (62.5%) patients with CFC syndrome had mutations (3 in KRAS, 24 in BRAF, and 8 in MAP2K1/2). No significant differences in clinical manifestations were found among 3 KRAS-positive patients, 16 BRAF-positive patients, and 6 MAP2K1/2-positive patients. Wrinkled palms and soles, hyperpigmentation and joint hyperextension, which have been commonly reported in Costello syndrome but not in CFC syndrome, were observed in 30-40% of the mutation-positive CFC patients, suggesting a significant clinical overlap between these two syndromes.
American Journal of Medical Genetics Part A 05/2007; 143A(8):799-807. · 2.39 Impact Factor
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Yoko Narumi,
Yoko Aoki,
Tetsuya Niihori,
Giovanni Neri,
Hélène Cavé,
Alain Verloes,
Caroline Nava,
Maria Ines Kavamura,
Nobuhiko Okamoto,
Kenji Kurosawa, [......],
Pablo Lapunzina,
Hirofumi Ohashi,
Yoshio Makita,
Ikuko Kondo,
Shigeru Tsuchiya,
Etsuro Ito,
Kiyoko Sameshima, Kumi Kato,
Shigeo Kure,
Yoichi Matsubara
[show abstract]
[hide abstract]
ABSTRACT: Cardio-facio-cutaneous (CFC) syndrome is a multiple congenital anomaly/mental retardation syndrome characterized by heart defects, a distinctive facial appearance, ectodermal abnormalities and mental retardation. Clinically, it overlaps with both Noonan syndrome and Costello syndrome, which are caused by mutations in two genes, PTPN11 and HRAS, respectively. Recently, we identified mutations in KRAS and BRAF in 19 of 43 individuals with CFC syndrome, suggesting that dysregulation of the RAS/RAF/MEK/ERK pathway is a molecular basis for CFC syndrome. The purpose of this study was to perform comprehensive mutation analysis in 56 patients with CFC syndrome and to investigate genotype–phenotype correlation. We analyzed KRAS, BRAF, and MAP2K1/2 (MEK1/2) in 13 new CFC patients and identified five BRAF and one MAP2K1 mutations in nine patients. We detected one MAP2K1 mutation in three patients and four new MAP2K2 mutations in four patients out of 24 patients without KRAS or BRAF mutations in the previous study [Niihori et al., 2006]. No mutations were identified in MAPK3/1 (ERK1/2) in 21 patients without any mutations. In total, 35 of 56 (62.5%) patients with CFC syndrome had mutations (3 in KRAS, 24 in BRAF, and 8 in MAP2K1/2). No significant differences in clinical manifestations were found among 3 KRAS-positive patients, 16 BRAF-positive patients, and 6 MAP2K1/2-positive patients. Wrinkled palms and soles, hyperpigmentation and joint hyperextension, which have been commonly reported in Costello syndrome but not in CFC syndrome, were observed in 30–40% of the mutation-positive CFC patients, suggesting a significant clinical overlap between these two syndromes. © 2007 Wiley-Liss, Inc.
American Journal of Medical Genetics Part A 03/2007; 143A(8):799 - 807. · 2.39 Impact Factor
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Shigeo Kure, Kumi Kato,
Agirios Dinopoulos,
Chuck Gail,
Ton J DeGrauw,
John Christodoulou,
Vladimir Bzduch,
Rozalia Kalmanchey,
Gyorgy Fekete,
Alex Trojovsky,
Barbara Plecko,
Galen Breningstall,
Jun Tohyama,
Yoko Aoki,
Yoichi Matsubara
[show abstract]
[hide abstract]
ABSTRACT: Nonketotic hyperglycinemia (NKH) is an inborn error of metabolism characterized by accumulation of glycine in body fluids and various neurological symptoms. NKH is caused by deficiency of the glycine cleavage multi-enzyme system with three specific components encoded by GLDC, AMT, and GCSH. We undertook the first comprehensive screening for GLDC, AMT, and GCSH mutations in 69 families (56, six, and seven families with neonatal, infantile, and late-onset type NKH, respectively). GLDC or AMT mutations were identified in 75% of neonatal and 83% of infantile families, but not in late-onset type NKH. No GCSH mutation was identified in this study. GLDC mutations were identified in 36 families, and AMT mutations were detected in 11 families. In 16 of the 36 families with GLDC mutations, mutations were identified in only one allele despite sequencing of the entire coding regions. The GLDC gene consists of 25 exons. Seven of the 32 GLDC missense mutations were clustered in exon 19, which encodes the cofactor-binding site Lys754. A large deletion involving exon 1 of the GLDC gene was found in Caucasian, Oriental, and black families. Multiple origins of the exon 1 deletion were suggested by haplotype analysis with four GLDC polymorphisms. This study provides a comprehensive picture of the genetic background of NKH as it is known to date.
Human Mutation 05/2006; 27(4):343-52. · 5.69 Impact Factor
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Tetsuya Niihori,
Yoko Aoki,
Yoko Narumi,
Giovanni Neri,
Hélène Cavé,
Alain Verloes,
Nobuhiko Okamoto,
Raoul C M Hennekam,
Gabriele Gillessen-Kaesbach,
Dagmar Wieczorek, [......],
Delphine Heron,
Dominique Bonneau,
Giuseppina Corona,
Tadashi Kaname,
Kenji Naritomi,
Clarisse Baumann,
Naomichi Matsumoto, Kumi Kato,
Shigeo Kure,
Yoichi Matsubara
[show abstract]
[hide abstract]
ABSTRACT: Cardio-facio-cutaneous (CFC) syndrome is characterized by a distinctive facial appearance, heart defects and mental retardation. It phenotypically overlaps with Noonan and Costello syndrome, which are caused by mutations in PTPN11 and HRAS, respectively. In 43 individuals with CFC, we identified two heterozygous KRAS mutations in three individuals and eight BRAF mutations in 16 individuals, suggesting that dysregulation of the RAS-RAF-ERK pathway is a common molecular basis for the three related disorders.
Nature Genetics 04/2006; 38(3):294-6. · 35.53 Impact Factor
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Fumiaki Kamada,
Shigeo Kure,
Takayuki Kudo,
Yoichi Suzuki,
Takeshi Oshima,
Akiko Ichinohe,
Kanako Kojima,
Tetsuya Niihori,
Junko Kanno,
Yoko Narumi,
Ayumi Narisawa, Kumi Kato,
Yoko Aoki,
Katsuhisa Ikeda,
Toshimitsu Kobayashi,
Yoichi Matsubara
[show abstract]
[hide abstract]
ABSTRACT: Autosomal-dominant, nonsyndromic hearing impairment is clinically and genetically heterogeneous. We encountered a large Japanese pedigree in which nonsyndromic hearing loss was inherited in an autosomal-dominant fashion. A genome-wide linkage study indicated linkage to the DFNA2 locus on chromosome 1p34. Mutational analysis of KCNQ4 encoding a potassium channel revealed a novel one-base deletion in exon 1, c.211delC, which generated a profoundly truncated protein without transmembrane domains (p.Q71fsX138). Previously, six missense mutations and one 13-base deletion, c.211_223del, had been reported in KCNQ4. Patients with the KCNQ4 missense mutations had younger-onset and more profound hearing loss than patients with the 211_223del mutation. In our current study, 12 individuals with the c.211delC mutation manifested late-onset and pure high-frequency hearing loss. Our results support the genotype-phenotype correlation that the KCNQ4 deletions are associated with later-onset and milder hearing impairment than the missense mutations. The phenotypic difference may be caused by the difference in pathogenic mechanisms: haploinsufficiency in deletions and dominant-negative effect in missense mutations.
Journal of Human Genetics 02/2006; 51(5):455-60. · 2.57 Impact Factor
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Yoko Aoki,
Tetsuya Niihori,
Hiroshi Kawame,
Kenji Kurosawa,
Hirofumi Ohashi,
Yukichi Tanaka,
Mirella Filocamo, Kumi Kato,
Yoichi Suzuki,
Shigeo Kure,
Yoichi Matsubara
[show abstract]
[hide abstract]
ABSTRACT: Costello syndrome is a multiple congenital anomaly and mental retardation syndrome characterized by coarse face, loose skin, cardiomyopathy and predisposition to tumors. We identified four heterozygous de novo mutations of HRAS in 12 of 13 affected individuals, all of which were previously reported as somatic and oncogenic mutations in various tumors. Our observations suggest that germline mutations in HRAS perturb human development and increase susceptibility to tumors.
Nature Genetics 11/2005; 37(10):1038-40. · 35.53 Impact Factor
