Novel ITGB4 Mutations in Lethal and Nonlethal Variants of Epidermolysis Bullosa with Pyloric Atresia: Missense versus Nonsense

Epidermolysis bullosa with pyloric atresia (EB-PA), an autosomal recessive genodermatosis, manifests with neonatal cutaneous blistering associated with congenital pyloric atresia. The disease is frequently lethal, but nonlethal cases have also been reported. Expression of the α6β4 integrin is altere...

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Veröffentlicht in:American journal of human genetics 1998-11, Vol.63 (5), p.1376-1387
Hauptverfasser: Pulkkinen, Leena, Rouan, Fatima, Bruckner-Tuderman, Leena, Wallerstein, Robert, Garzon, Maria, Brown, Tod, Smith, Lynne, Carter, William, Uitto, Jouni
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container_issue 5
container_start_page 1376
container_title American journal of human genetics
container_volume 63
creator Pulkkinen, Leena
Rouan, Fatima
Bruckner-Tuderman, Leena
Wallerstein, Robert
Garzon, Maria
Brown, Tod
Smith, Lynne
Carter, William
Uitto, Jouni
description Epidermolysis bullosa with pyloric atresia (EB-PA), an autosomal recessive genodermatosis, manifests with neonatal cutaneous blistering associated with congenital pyloric atresia. The disease is frequently lethal, but nonlethal cases have also been reported. Expression of the α6β4 integrin is altered at the dermal-epidermal basement-membrane zone; recently, mutations in the corresponding genes (ITGA6 and ITGB4) have been disclosed in a limited number of patients, premature termination codons in both alleles being characteristic of lethal variants. In this study, we have examined the molecular basis of EB-PA in five families, two of them with lethal and three of them with nonlethal variants of the disease. Mutation analysis disclosed novel lesions in both ITGB4 alleles of each proband. One of the patients with lethal EB-PA was a compound heterozygote for premature termination–codon mutations (C738X/4791delCA), whereas the other patient with a lethal variant was homozygous for a missense mutation involving a cysteine residue (C61Y). The three nonlethal cases had missense mutations in both alleles (C562R/C562R, R1281W/R252C, and R1281W/R1281W). Immunofluorescence staining of skin in two of the nonlethal patients and in one of the lethal cases was positive, yet attenuated, for α6 and β4 integrins. These results confirm that ITGB4 mutations underlie EB-PA and show that missense mutations may lead to nonlethal phenotypes.
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The disease is frequently lethal, but nonlethal cases have also been reported. Expression of the α6β4 integrin is altered at the dermal-epidermal basement-membrane zone; recently, mutations in the corresponding genes (ITGA6 and ITGB4) have been disclosed in a limited number of patients, premature termination codons in both alleles being characteristic of lethal variants. In this study, we have examined the molecular basis of EB-PA in five families, two of them with lethal and three of them with nonlethal variants of the disease. Mutation analysis disclosed novel lesions in both ITGB4 alleles of each proband. One of the patients with lethal EB-PA was a compound heterozygote for premature termination–codon mutations (C738X/4791delCA), whereas the other patient with a lethal variant was homozygous for a missense mutation involving a cysteine residue (C61Y). The three nonlethal cases had missense mutations in both alleles (C562R/C562R, R1281W/R252C, and R1281W/R1281W). Immunofluorescence staining of skin in two of the nonlethal patients and in one of the lethal cases was positive, yet attenuated, for α6 and β4 integrins. 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Immunofluorescence staining of skin in two of the nonlethal patients and in one of the lethal cases was positive, yet attenuated, for α6 and β4 integrins. These results confirm that ITGB4 mutations underlie EB-PA and show that missense mutations may lead to nonlethal phenotypes.</abstract><cop>Chicago, IL</cop><pub>Elsevier Inc</pub><pmid>9792864</pmid><doi>10.1086/302116</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record>
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subjects Antigens, CD - genetics
Antigens, Surface - genetics
Biological and medical sciences
Blister
Blistering skin diseases
Child
Codon, Nonsense
Consanguinity
Cutaneous basement-membrane zone
Dermatology
Digestive System Abnormalities - genetics
Epidermolysis bullosa with pyloric atresia
Epidermolysis Bullosa, Junctional - genetics
Female
Gendodermatosis
Genetic Variation
Hereditary diseases of the skin. Congenital diseases of the skin. Haemangioma of the skin, of mucosae and of soft tissue
Heteroduplex analysis
Humans
Infant
Infant, Newborn
Integrin alpha6beta4
Integrin beta4
Integrins - genetics
Male
Medical sciences
Mutation, Missense
Polymerase Chain Reaction
Pylorus - abnormalities
Skin - pathology
Syndrome
β4 integrin mutations
title Novel ITGB4 Mutations in Lethal and Nonlethal Variants of Epidermolysis Bullosa with Pyloric Atresia: Missense versus Nonsense
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