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Whole-exome sequencing diagnosis of two autosomal recessive disorders in one family
Abstracts / Journal of Dermatological Science 84 (2016) e89–e180
a slight decrease of pyknotic nuclei and it prevents the detachment of the dermo-epidermal junction induced by the pollutants which are composed of heavy metals and hydrocarbons. It also induces a slight increase of collagen density when compared to the batch treated with pollutants. In parallel it induces a quite clear increase of collagen I and a very clear decrease of MMP-1comparatively to the blank batch treated with pollutants. Finally it decrease MDA (lipid peroxidation marker) quantity in the culture medium when compared to the pollutants-treated batch. Without pollution stress, the product CJFE significantly reduces the basal oxidative stress level by 16%. These results suggest that CJFE may be considered as an active ingredient for anti-aging effects and pollution-protecting cosmetic products.
sis revealed that dermal fibroblasts (DFs) from ZEB2 cKO mice expressed decreased collagen 1 and 3 genes but increased MMP13 gene. Electron micrographs of the dermis of ZEB2 cKO mice showed collagen fibrils with abnormally small diameters, resembling them in a MOWS patient. Finally, ZEB2 cKO mice showed impaired fibrogenesis by subcutaneous injection of bleomycin. These results suggest that ZEB2 contributes to de novo and induced collagenogenesis, and more importantly, that MOWS is relevant to a novel subtype of EDS. http://dx.doi.org/10.1016/j.jdermsci.2016.08.416 P07-02[C05-06]
http://dx.doi.org/10.1016/j.jdermsci.2016.08.415
Whole-exome sequencing diagnosis of two autosomal recessive disorders in one family
Category 7 (P07): Genetic Disease/Gene Regulation and Gene Therapy
Takuya Takeichi 1,2,∗ , Arti Nanda 3 , Masashi Akiyama 2 , Hejab Al-Ajmi 3 , John A. McGrath 1
P07-01[II-4] Mutations of zinc finger E-box binding homeobox 2 (ZEB2) leading to develop connecting tissue disorder similar to Ehlers–Danlos syndrome Mika Teraishi 1,∗ , Mikiro Takaishi 1 , Kimiko Nakajima 1 , Seiji Mizuno 2 , Yoko Hiraki 3 , Toshiyuki Fukada 4 , Shinji Shimoda 5 , Yoshinobu Asada 6 , Nobuaki Wakamatsu 2 , Takahisa Furukawa 7 , Shigetoshi Sano 1 1 Department of Dermatology, Kochi Medical School, Kochi University, Nankoku, Japan 2 Department of Clinical Genetics, Central Hospital, Aichi Human Service Center, Kasugai, Japan 3 Hiroshima Municipal Center for Child Health and Development, Hiroshima, Japan 4 Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan 5 Department of Anatomy-1, Tsurumi University School of Dental Medicine, Yokohama, Japan 6 Department of Pediatric Dentistry, Tsurumi University School of Dental Medicine, Yokohama, Japan 7 Laboratory for Molecular and Developmental Biology, Institute for Protein Research, Osaka University, Suita, Japan
Mowat–Wilson syndrome (MOWS, OMIM#235730) is a multiple congenital anomaly syndrome characterized by distinctive facial appearance, intellectual disability, microcephaly, and variable congenital malformations, including congenital heart defects and Hirschsprung disease. It is caused by heterozygous loss of function mutations or deletions in ZEB2. Whereas no skin manifestation of MOWS has been documented, we found for the first time that MOWS patients harbored hyperextensibility and fragility of the skin, being similar to Ehlers–Danlos syndrome (EDS). Transmission electron microscopy analysis of skin from a MOWS patient revealed dermal collagen fibrils with markedly decreased diameters. To study the role of ZEB2 in collagenogenesis, ZEB2 conditional knockout (cKO) mice were generated by crossing ZEB2flox/flox mice with Cre mice under the control of prx 1 promoter, to target the mesoderm. Newborn ZEB2 cKO mice were small and demonstrated abnormalities in the teeth and scalp bone. Notably, the skin of ZEB2 cKO mice appeared flabby and hyperextesiblity, and histologic examination revealed hypoplasia of the dermis. qRT-PCR analy-
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1 St Johns Institute of Dermatology, Kings College London, Guys Hospital, London, UK 2 Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan 3 Asad Al-Hamad Dermatology Center, Al-Sabah Hospital, Kuwait
Autosomal recessive congenital ichthyosis (ARCI) is a genetically heterogeneous disorder for which subtyping through molecular analysis can help determine the eventual phenotype and prognosis. We used whole-exome sequencing to identify a new homozygous donor splice- site mutation in ST14 (IVS5+1G>A), encoding matriptase, in a 4-year-old girl with ARCI from a parent-related Kuwaiti family. Clinically, she also had hypotrichosis, which supported a diagnosis of ARCI type 11. Both parents were asymptomatic heterozygous carriers of this mutation in ST14 . Only four previous examples of pathogenic mutations in ST14 have been reported, and our findings expand genotype–phenotype correlation for this subtype of ARCI. There was also an additional unresolved genetic disorder in this family. Our patient with ARCI was the second child born to these parents; the first (deceased) and third children had congenital brain and eye abnormalities of uncertain aetiology and with no precise diagnosis. Further analysis of our patient’s exome dataset revealed heterozygosity for a donor splice-site mutation in POMT1 (IVS4+1G>T), encoding the protein O-mannosyltransferase, a gene (and specific mutation) implicated in autosomal recessive Walker–Warburg syndrome. DNA sequencing in the third child showed homozygosity for this mutation in POMT1 . The parents were both heterozygous for this mutation in POMT1. In this family, whole-exome sequencing provided accurate subtyping of a form of ARCI in one child and generated an explanation for an undiagnosed developmental disorder in two other children, findings that improve the prospects for diagnostic accuracy, genetic counselling, and dual prenatal testing, as well as demonstrating the impact of next-generation sequencing technologies on clinical genetics. http://dx.doi.org/10.1016/j.jdermsci.2016.08.417
a slight decrease of pyknotic nuclei and it prevents the detachment of the dermo-epidermal junction induced by the pollutants which are composed of heavy metals and hydrocarbons. It also induces a slight increase of collagen density when compared to the batch treated with pollutants. In parallel it induces a quite clear increase of collagen I and a very clear decrease of MMP-1comparatively to the blank batch treated with pollutants. Finally it decrease MDA (lipid peroxidation marker) quantity in the culture medium when compared to the pollutants-treated batch. Without pollution stress, the product CJFE significantly reduces the basal oxidative stress level by 16%. These results suggest that CJFE may be considered as an active ingredient for anti-aging effects and pollution-protecting cosmetic products.
sis revealed that dermal fibroblasts (DFs) from ZEB2 cKO mice expressed decreased collagen 1 and 3 genes but increased MMP13 gene. Electron micrographs of the dermis of ZEB2 cKO mice showed collagen fibrils with abnormally small diameters, resembling them in a MOWS patient. Finally, ZEB2 cKO mice showed impaired fibrogenesis by subcutaneous injection of bleomycin. These results suggest that ZEB2 contributes to de novo and induced collagenogenesis, and more importantly, that MOWS is relevant to a novel subtype of EDS. http://dx.doi.org/10.1016/j.jdermsci.2016.08.416 P07-02[C05-06]
http://dx.doi.org/10.1016/j.jdermsci.2016.08.415
Whole-exome sequencing diagnosis of two autosomal recessive disorders in one family
Category 7 (P07): Genetic Disease/Gene Regulation and Gene Therapy
Takuya Takeichi 1,2,∗ , Arti Nanda 3 , Masashi Akiyama 2 , Hejab Al-Ajmi 3 , John A. McGrath 1
P07-01[II-4] Mutations of zinc finger E-box binding homeobox 2 (ZEB2) leading to develop connecting tissue disorder similar to Ehlers–Danlos syndrome Mika Teraishi 1,∗ , Mikiro Takaishi 1 , Kimiko Nakajima 1 , Seiji Mizuno 2 , Yoko Hiraki 3 , Toshiyuki Fukada 4 , Shinji Shimoda 5 , Yoshinobu Asada 6 , Nobuaki Wakamatsu 2 , Takahisa Furukawa 7 , Shigetoshi Sano 1 1 Department of Dermatology, Kochi Medical School, Kochi University, Nankoku, Japan 2 Department of Clinical Genetics, Central Hospital, Aichi Human Service Center, Kasugai, Japan 3 Hiroshima Municipal Center for Child Health and Development, Hiroshima, Japan 4 Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan 5 Department of Anatomy-1, Tsurumi University School of Dental Medicine, Yokohama, Japan 6 Department of Pediatric Dentistry, Tsurumi University School of Dental Medicine, Yokohama, Japan 7 Laboratory for Molecular and Developmental Biology, Institute for Protein Research, Osaka University, Suita, Japan
Mowat–Wilson syndrome (MOWS, OMIM#235730) is a multiple congenital anomaly syndrome characterized by distinctive facial appearance, intellectual disability, microcephaly, and variable congenital malformations, including congenital heart defects and Hirschsprung disease. It is caused by heterozygous loss of function mutations or deletions in ZEB2. Whereas no skin manifestation of MOWS has been documented, we found for the first time that MOWS patients harbored hyperextensibility and fragility of the skin, being similar to Ehlers–Danlos syndrome (EDS). Transmission electron microscopy analysis of skin from a MOWS patient revealed dermal collagen fibrils with markedly decreased diameters. To study the role of ZEB2 in collagenogenesis, ZEB2 conditional knockout (cKO) mice were generated by crossing ZEB2flox/flox mice with Cre mice under the control of prx 1 promoter, to target the mesoderm. Newborn ZEB2 cKO mice were small and demonstrated abnormalities in the teeth and scalp bone. Notably, the skin of ZEB2 cKO mice appeared flabby and hyperextesiblity, and histologic examination revealed hypoplasia of the dermis. qRT-PCR analy-
e139
1 St Johns Institute of Dermatology, Kings College London, Guys Hospital, London, UK 2 Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan 3 Asad Al-Hamad Dermatology Center, Al-Sabah Hospital, Kuwait
Autosomal recessive congenital ichthyosis (ARCI) is a genetically heterogeneous disorder for which subtyping through molecular analysis can help determine the eventual phenotype and prognosis. We used whole-exome sequencing to identify a new homozygous donor splice- site mutation in ST14 (IVS5+1G>A), encoding matriptase, in a 4-year-old girl with ARCI from a parent-related Kuwaiti family. Clinically, she also had hypotrichosis, which supported a diagnosis of ARCI type 11. Both parents were asymptomatic heterozygous carriers of this mutation in ST14 . Only four previous examples of pathogenic mutations in ST14 have been reported, and our findings expand genotype–phenotype correlation for this subtype of ARCI. There was also an additional unresolved genetic disorder in this family. Our patient with ARCI was the second child born to these parents; the first (deceased) and third children had congenital brain and eye abnormalities of uncertain aetiology and with no precise diagnosis. Further analysis of our patient’s exome dataset revealed heterozygosity for a donor splice-site mutation in POMT1 (IVS4+1G>T), encoding the protein O-mannosyltransferase, a gene (and specific mutation) implicated in autosomal recessive Walker–Warburg syndrome. DNA sequencing in the third child showed homozygosity for this mutation in POMT1 . The parents were both heterozygous for this mutation in POMT1. In this family, whole-exome sequencing provided accurate subtyping of a form of ARCI in one child and generated an explanation for an undiagnosed developmental disorder in two other children, findings that improve the prospects for diagnostic accuracy, genetic counselling, and dual prenatal testing, as well as demonstrating the impact of next-generation sequencing technologies on clinical genetics. http://dx.doi.org/10.1016/j.jdermsci.2016.08.417