title: Viable phenotype of ILNEB syndrome without nephrotic impairment in siblings heterozygous for unreported integrin alpha3 mutations.
abstract: Integrin α3 (ITGA3) gene mutations are associated with Interstitial Lung disease, Nephrotic syndrome and Epidermolysis bullosa (ILNEB syndrome). To date only six patients are reported: all carried homozygous ITGA3 mutations and presented a dramatically severe phenotype leading to death before age 2 years, from multi-organ failure due to interstitial lung disease and congenital nephrotic syndrome. The involvement of skin and cutaneous adnexa was variable with sparse hair and nail dysplasia combined or not to skin lesions ranging from skin fragility to epidermolysis bullosa-like blistering.
  
  
  
  We report on two siblings of 13 and 9 years born to non-consanguineous healthy parents, who display growth delay, severe pulmonary fibrosis with fatigue, dyspnea on exertion and wheezing, atrophic skin with erythematosus lesions, rare eyelashes/eyebrows and pachyonychia. By exome sequencing, we identified two unreported ITGA3 missense mutations, c.373G>A (p.(G125R)) in exon 3 and c.821G>A (p.(R274Q)) in exon 6, affecting highly conserved residues in the integrin α3 extracellular N-terminal β-propeller domain. Homology modelling of α3β1 heterodimer fragment, encompassing the mutation sites, showed that G125 plays a pivotal structural role in the β-propeller, while R274 might prevent the interaction between integrin and urokinase complex.
  
  
  
  We report a variant of ILNEB syndrome in two siblings differing from the previously reported patients in the lack of nephrotic impairment and survival beyond childhood. Our siblings are the first reported compound heterozygous for ITGA3 mutations; this state as well as the hypomorphic nature of their p.(R274Q) mutation likely account for their survival.
authors.affiliation: Dipartimento di Scienze della Salute, Università degli Studi di Milano, Via Antonio di Rudinì 8, 20142, Milan, Italy. elisaadele.colombo@unimi.it.
authors.forename: Elisa Adele
authors.initials: EA
authors.lastname: Colombo
authors.affiliation: Genetica Medica, Ospedale Buzzi, Azienda Ospedaliera Istituti Clinici di perfezionamento, Via Castelvetro 32, 20154, Milan, Italy.
authors.forename: Luigina
authors.initials: L
authors.lastname: Spaccini
authors.affiliation: Dipartimento di Biotecnologie Mediche e di Medicina Traslazionale, Università degli Studi di Milano, Via Viotti 3/5, 20133, Milan, Italy.
authors.forename: Ludovica
authors.initials: L
authors.lastname: Volpi
authors.affiliation: Dipartimento di Scienze della Salute, Università degli Studi di Milano, Via Antonio di Rudinì 8, 20142, Milan, Italy.
authors.forename: Gloria
authors.initials: G
authors.lastname: Negri
authors.affiliation: Center for Translational Genomics and BioInformatics, San Raffaele Scientific Institute, Via Olgettina 60, 20132, Milan, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Cittaro
authors.affiliation: Center for Translational Genomics and BioInformatics, San Raffaele Scientific Institute, Via Olgettina 60, 20132, Milan, Italy.
authors.forename: Dejan
authors.initials: D
authors.lastname: Lazarevic
authors.affiliation: SC Radiologia e Neuroradiologia Pediatrica, Ospedale Buzzi, Azienda Ospedaliera Istituti Clinici di perfezionamento, Via Castelvetro 32, 20154, Milan, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Zirpoli
authors.affiliation: Dipartmento di Pediatria, Ospedale Buzzi, Azienda Ospedaliera Istituti Clinici di perfezionamento, Via Castelvetro 32, 20154, Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Farolfi
authors.affiliation: Dipartimento di Scienze della Salute, Università degli Studi di Milano, Via Antonio di Rudinì 8, 20142, Milan, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Gervasini
authors.affiliation: Dipartimento di Biologia, Università degli Studi di Napoli Federico II, Cupa Nuova Cintia 21, 80126, Naples, Italy.
authors.forename: Maria Vittoria
authors.initials: MV
authors.lastname: Cubellis
authors.affiliation: Laboratorio di Citogenetica Medica e Genetica Molecolare, Centro di Ricerche e Tecnologie Biomediche IRCCS-Istituto Auxologico Italiano, Via Zucchi 18, 20095, Cusano Milanino, Italy.
authors.forename: Lidia
authors.initials: L
authors.lastname: Larizza
mesh_terms: D000293:Adolescent; D002648:Child; D004820:Epidermolysis Bullosa / Q000235:genetics* / Q000473:pathology; D005260:Female; D006579:Heterozygote; D006801:Humans; D039422:Integrin alpha3 / Q000235:genetics / Q000378:metabolism*; D017563:Lung Diseases, Interstitial / Q000235:genetics* / Q000473:pathology; D008297:Male; D020125:Mutation, Missense; D009404:Nephrotic Syndrome / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D035781:Siblings
chemical_list: D039422:Integrin alpha3
keywords: ILNEB variant; Integrin α3; Lung disease; Skin alterations; Whole-exome sequencing