From our cohort of patients with a clinical diagnosis suggestive for the two partially overlapping genodermatoses, Rothmund-Thomson Syndrome (RTS) and Poikiloderma with Neutropenia (PN), we have selected 11 patients without mutations in RECQ4 and USB1 genes causative for RTS and PN, respectively, to perform whole exome sequencing (WES). Here we report on a family with two affected siblings of 12 and 8 years born from non-consanguineous healthy parents. Both siblings display growth delay, severe pulmonary fibrosis with respiratory failure and dermatological alterations (atrophic skin with erythematosus lesions, rare eyelashes and eyebrows, pachionychia). Thanks to WES, we have identified two novel missense mutations in the Integrin 3 gene (ITGA3): c.373G>A (p.G125R) in exon 3 and c.821G>A (p.R274Q) in exon 6 of maternal and paternal origin, respectively. Both substitutions affect highly conserved residues located in the second and in the fourth FG-GAP motif of the extracellular N-terminal 7-bladed -propeller domain., with the p.R274Q in the fourth FG-GAP repeat. Sanger sequencing confirmed the presence of the two variants in the sibs and the carrier status of the parents. Neither alteration is recorded in polymorphism databases, (Ensembl, dbSNPs, 1000 Genomes), and is present in a set of 200 run exomes. PolyPhen, SIFT, PMut and SNP&GO algorithms predicted the p.G125R mutation to be damaging, while the p.R274Q mutation was scored damaging only by PolyPhen and SNP&GO. mRNA analysis confirmed the presence of both mutated transcripts. In literature, only four patients with homozygous ITGA3 mutations have been reported (Has 2012, NEJM; Nicolaou 2012, J Clin Invest), all with a clinical presentation partially overlapping with that of our patients, but dramatically more severe. All displayed a fatal multiorgan disorder, characterized by skin lesions, congenital nephrotic syndrome and interstitial lung disease, leading to premature death before age 2 years. The skin was involved in the form of fragility or epidermolysis bullosa-like lesions in two out of four reported cases, whereas in the others two no alterations were reported. Conversely, our sibs display marked skin lesion and interstitial lung disease with respiratory distress but do not show renal signs which likely accounts for their management and survival.
VIABLE PHENOTYPE ASSOCIATED WITH NOVEL MUTATIONS OF INTEGRIN 3, ENCODING A LAMININS RECEPTOR INVOLVED IN STRUCTURAL AND FUNCTIONAL ORGANIZATION OF LUNG, KIDNEY AND SKIN EPITHELIA / E. Colombo, L. Spaccini, G. Negri, L. Volpi, C. Gervasini, D. Lazarevic, A. Farolfi, D. Cittaro, L. Larizza - In: “Il Sequenziamento di Nuova Generazione in Genetica Umana e Medica” (Evento SIGU) – Bologna, 30-31 Ottobre 2014[s.l] : SIGU - Società Italiana di Genetica Umana, 2014 Oct 31. (( convegno “Il Sequenziamento di Nuova Generazione in Genetica Umana e Medica” (Evento SIGU) tenutosi a Bologna nel 2014.
|Titolo:||VIABLE PHENOTYPE ASSOCIATED WITH NOVEL MUTATIONS OF INTEGRIN 3, ENCODING A LAMININS RECEPTOR INVOLVED IN STRUCTURAL AND FUNCTIONAL ORGANIZATION OF LUNG, KIDNEY AND SKIN EPITHELIA|
|Settore Scientifico Disciplinare:||Settore MED/03 - Genetica Medica|
|Data di pubblicazione:||31-ott-2014|
|Tipologia:||Book Part (author)|
|Appare nelle tipologie:||03 - Contributo in volume|