Harlequin ichthyosis(HI)is one of the most devastating genodermatoses.Recently,ABCA12 mutations were identifiedas the cause of HI.A newborn Japanese male demonstrated the typical features of HI.The patient was treated...Harlequin ichthyosis(HI)is one of the most devastating genodermatoses.Recently,ABCA12 mutations were identifiedas the cause of HI.A newborn Japanese male demonstrated the typical features of HI.The patient was treated with oral etretinate and his general condition has been good(now aged 1.5 years).This patient with moderate clinical severity was compound heterozygous for a novel de novo missense mutation 1160G > A(S387N)in exon 10 and a maternal deletion mutation 4158 4160delTAC(T1387del)in exon 28 of ABCA12.T1387del was a deletion of a highly conserved threonine residue within the first adenosine 5’triphosphate-binding domain and is thought to seriously affect the function of the ABCA12 protein.Conversely,the residue 387 is located outside the known active sites of ABCA12 and S387N is predicted not to lead to a serious functional deficiency in ABCA12.Electron microscopy revealed abnormal lamellar granules in the granular layer cells and a moderate number of lipid vacuoles in the cornified cells.Disturbed glucosylceramide transport was confirmed in the cultured keratinocytes from the patient.No de novomutation in ABCA12 has yet been reported either in HI or lamellar ichthyosis.The present case suggested that a de novo ABCA12 mutation might underlie HI.展开更多
Harlequin ichthyosis (HI) is a severe genetic skin disorder and caused by mutation in the ATP-binding cassette A12 (ABCA12) gene. The retinoid administration has dramatically improved long-term survival of HI, but imp...Harlequin ichthyosis (HI) is a severe genetic skin disorder and caused by mutation in the ATP-binding cassette A12 (ABCA12) gene. The retinoid administration has dramatically improved long-term survival of HI, but improvements are still needed. However, the ABCA12 null mice failed to respond to retinoid treatment, which impedes the development of novel cure strategies for HI. Here we generated an ethylnitrosourea mutagenic HI pig model (named Z9), which carries a novel deep intronic mutation IVS49-727 A>G in the ABCA12 gene, resulting in abnormal mRNA splicing and truncated protein production. Z9 pigs exhibit significant clinical symptom as human patients with HI. Most importantly, systemic retinoid treatment significantly prolonged the life span of the mutant pigs via improving epidermal maturation, decreasing epidermal apoptosis, and triggering the expression of ABCA6. Taken together, this pig model perfectly resembles the clinical symptom and molecular pathology of patients with HI and will be useful for understanding mechanistic insight and developing therapeutic strategies.展开更多
Introduction:Congenital ichthyosiform erythroderma(CIE)is characterized by fine,whitish scales on a background of erythematous skin over the whole body;it is reportedly caused by mutations inABCA12,ALOX12B,ALOXE3,CERS...Introduction:Congenital ichthyosiform erythroderma(CIE)is characterized by fine,whitish scales on a background of erythematous skin over the whole body;it is reportedly caused by mutations inABCA12,ALOX12B,ALOXE3,CERS3,CYP4F22,NIPAL4,PNPLA1,andTGM1 genes.Case presentation:A 15-month-old girl presented with CIE associated with compound heterozygousABCA12 mutations,a known missense mutation c.4139A>G(p.Asn1380Ser)from her father,and a novel missense mutation c.4300A>G(p.Thr1434Ala)from her mother.Conclusion:This is the first report to indicate that compound heterozygous missense mutations in the first ATP-binding cassette ofABCA12 could contribute to the onset of CIE.展开更多
Harlequin ichthyosis is a severe autosomal recessive skin disorder.Most deaths occur within the first few days after birth,and the survivors still have severe chronic skin disease throughout their lives.Almost all cas...Harlequin ichthyosis is a severe autosomal recessive skin disorder.Most deaths occur within the first few days after birth,and the survivors still have severe chronic skin disease throughout their lives.Almost all cases were associated with a pathogenic variant of adenosine triphosphate binding cassette transporter,subfamily A,member 12(ABCA12)gene.We described a case of HI diagnosed by ultrasound examination during the second-trimester and genetic diagnosis reveal two novel heterozygous ABCA12 mutations c.2563-2570delinsGGCAATT,p.(Leu855Glyfs*13),and c.6116delT,p.(Met2039Argfs*8)by the next-generation DNA sequencing,which further enriched our understanding of the pathogenic variation of ABCA12 gene.展开更多
文摘Harlequin ichthyosis(HI)is one of the most devastating genodermatoses.Recently,ABCA12 mutations were identifiedas the cause of HI.A newborn Japanese male demonstrated the typical features of HI.The patient was treated with oral etretinate and his general condition has been good(now aged 1.5 years).This patient with moderate clinical severity was compound heterozygous for a novel de novo missense mutation 1160G > A(S387N)in exon 10 and a maternal deletion mutation 4158 4160delTAC(T1387del)in exon 28 of ABCA12.T1387del was a deletion of a highly conserved threonine residue within the first adenosine 5’triphosphate-binding domain and is thought to seriously affect the function of the ABCA12 protein.Conversely,the residue 387 is located outside the known active sites of ABCA12 and S387N is predicted not to lead to a serious functional deficiency in ABCA12.Electron microscopy revealed abnormal lamellar granules in the granular layer cells and a moderate number of lipid vacuoles in the cornified cells.Disturbed glucosylceramide transport was confirmed in the cultured keratinocytes from the patient.No de novomutation in ABCA12 has yet been reported either in HI or lamellar ichthyosis.The present case suggested that a de novo ABCA12 mutation might underlie HI.
基金the Strategic Priority Research Programs of CAS(XDA16030300)the National Natural Science Foundation of China(81671274,31272440,and 31801031)+1 种基金the National Transgenic Project of China(2016ZX08009003-006-007)the Elite Youth Program of the Chinese Academy of Agricultural Sciences(ASTIP-IAS05).
文摘Harlequin ichthyosis (HI) is a severe genetic skin disorder and caused by mutation in the ATP-binding cassette A12 (ABCA12) gene. The retinoid administration has dramatically improved long-term survival of HI, but improvements are still needed. However, the ABCA12 null mice failed to respond to retinoid treatment, which impedes the development of novel cure strategies for HI. Here we generated an ethylnitrosourea mutagenic HI pig model (named Z9), which carries a novel deep intronic mutation IVS49-727 A>G in the ABCA12 gene, resulting in abnormal mRNA splicing and truncated protein production. Z9 pigs exhibit significant clinical symptom as human patients with HI. Most importantly, systemic retinoid treatment significantly prolonged the life span of the mutant pigs via improving epidermal maturation, decreasing epidermal apoptosis, and triggering the expression of ABCA6. Taken together, this pig model perfectly resembles the clinical symptom and molecular pathology of patients with HI and will be useful for understanding mechanistic insight and developing therapeutic strategies.
基金National Natural Science Foundation of China(No.81673042)。
文摘Introduction:Congenital ichthyosiform erythroderma(CIE)is characterized by fine,whitish scales on a background of erythematous skin over the whole body;it is reportedly caused by mutations inABCA12,ALOX12B,ALOXE3,CERS3,CYP4F22,NIPAL4,PNPLA1,andTGM1 genes.Case presentation:A 15-month-old girl presented with CIE associated with compound heterozygousABCA12 mutations,a known missense mutation c.4139A>G(p.Asn1380Ser)from her father,and a novel missense mutation c.4300A>G(p.Thr1434Ala)from her mother.Conclusion:This is the first report to indicate that compound heterozygous missense mutations in the first ATP-binding cassette ofABCA12 could contribute to the onset of CIE.
基金Cultivating funding of the First Affiliated Hospital of Chongqing Medical University(PYJJ2017-33)
文摘Harlequin ichthyosis is a severe autosomal recessive skin disorder.Most deaths occur within the first few days after birth,and the survivors still have severe chronic skin disease throughout their lives.Almost all cases were associated with a pathogenic variant of adenosine triphosphate binding cassette transporter,subfamily A,member 12(ABCA12)gene.We described a case of HI diagnosed by ultrasound examination during the second-trimester and genetic diagnosis reveal two novel heterozygous ABCA12 mutations c.2563-2570delinsGGCAATT,p.(Leu855Glyfs*13),and c.6116delT,p.(Met2039Argfs*8)by the next-generation DNA sequencing,which further enriched our understanding of the pathogenic variation of ABCA12 gene.
