Viable phenotype of ILNEB syndrome without nephrotic impairment in siblings heterozygous for unreported integrin alpha3 mutations

Elisa A. Colombo, L. Spaccini, Ludovica Volpi, Gloria Negri, Davide Cittaro, Dejan Lazarevic, Salvatore Zirpoli, Andrea Farolfi, Cristina Gervasini, M. Vittoria Cubellis, Lidia Larizza

Research output: Contribution to journalArticle

Abstract

Background: Integrin a3 (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. Results: 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 a3 extracellular N-terminal ß-propeller domain. Homology modelling of a3ß1 heterodimer fragment, encompassing the mutation sites, showed that G125 plays a pivotal structural role in the ß-propeller, while R274 might prevent the interaction between integrin and urokinase complex. Conclusion: 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.

Original languageEnglish
Pages (from-to)1-9
Number of pages9
JournalOrphanet Journal of Rare Diseases
Volume11
Issue number1
DOIs
Publication statusPublished - Oct 7 2016

Fingerprint

Integrin alpha3
Nephrotic Syndrome
Integrins
Siblings
Phenotype
Mutation
Skin
Epidermolysis Bullosa
Interstitial Lung Diseases
Exons
Malformed Nails
Eyelashes
Exome
Eyebrows
Survival
Pulmonary Fibrosis
Respiratory Sounds
Urokinase-Type Plasminogen Activator
Missense Mutation
Nails

Keywords

  • ILNEB variant
  • Integrin a3
  • Lung disease
  • Skin alterations
  • Whole-exome sequencing

ASJC Scopus subject areas

  • Medicine(all)
  • Genetics(clinical)
  • Pharmacology (medical)

Cite this

Viable phenotype of ILNEB syndrome without nephrotic impairment in siblings heterozygous for unreported integrin alpha3 mutations. / Colombo, Elisa A.; Spaccini, L.; Volpi, Ludovica; Negri, Gloria; Cittaro, Davide; Lazarevic, Dejan; Zirpoli, Salvatore; Farolfi, Andrea; Gervasini, Cristina; Vittoria Cubellis, M.; Larizza, Lidia.

In: Orphanet Journal of Rare Diseases, Vol. 11, No. 1, 07.10.2016, p. 1-9.

Research output: Contribution to journalArticle

Colombo, Elisa A. ; Spaccini, L. ; Volpi, Ludovica ; Negri, Gloria ; Cittaro, Davide ; Lazarevic, Dejan ; Zirpoli, Salvatore ; Farolfi, Andrea ; Gervasini, Cristina ; Vittoria Cubellis, M. ; Larizza, Lidia. / Viable phenotype of ILNEB syndrome without nephrotic impairment in siblings heterozygous for unreported integrin alpha3 mutations. In: Orphanet Journal of Rare Diseases. 2016 ; Vol. 11, No. 1. pp. 1-9.
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abstract = "Background: Integrin a3 (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. Results: 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 a3 extracellular N-terminal {\ss}-propeller domain. Homology modelling of a3{\ss}1 heterodimer fragment, encompassing the mutation sites, showed that G125 plays a pivotal structural role in the {\ss}-propeller, while R274 might prevent the interaction between integrin and urokinase complex. Conclusion: 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.",
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AU - Spaccini, L.

AU - Volpi, Ludovica

AU - Negri, Gloria

AU - Cittaro, Davide

AU - Lazarevic, Dejan

AU - Zirpoli, Salvatore

AU - Farolfi, Andrea

AU - Gervasini, Cristina

AU - Vittoria Cubellis, M.

AU - Larizza, Lidia

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AB - Background: Integrin a3 (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. Results: 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 a3 extracellular N-terminal ß-propeller domain. Homology modelling of a3ß1 heterodimer fragment, encompassing the mutation sites, showed that G125 plays a pivotal structural role in the ß-propeller, while R274 might prevent the interaction between integrin and urokinase complex. Conclusion: 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.

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