A novel model of nephrotic syndrome results from a point mutation in Lama5 and is modified by genetic background

Falcone, Sara; Nicol, T.; Blease, Andrew; Randles, Michael J.; Angus, Elizabeth M.; Page, Anton; Tam, Frederick W.K.; Pusey, Charles D.; Lennon, Rachel; Potter, Paul K.

doi:10.1016/j.kint.2021.10.031

Cited by 6 publications

(5 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This missense mutation is in the L4a subunit, where other pathogenic missense variants have been reported in humans and mice. Analysis of a murine model generated by Falcone et al with an L4a domain variant (Gly3685Arg) showed depletion of laminin α5 and different protein composition and organization of the GBM compared to wild mice ( 12 ). Falcone et al postulated that altered GBM properties might form a more fluid matrix that subjects podocytes to more mechanical stress, leading to the nephrotic phenotype.…”

Section: Discussionmentioning

confidence: 99%

“…Podocyte-specific inactivation of LAMA5 produced proteinuria in mice, their kidneys showing foot process effacement and a thick and thin “moth-eaten” appearance of GBM ( 11 ). Mice with biallelic LAMA5 mutations in the L4a domain (Glu884Gly) showed reduced secretion of the laminin α5β2γ1 heterotrimer and, in turn, altered GBM composition ( 12 ). Following the first connection of LAMA5 to human kidney disease in an adult female with focal segmental glomerulosclerosis (FSGS) in 2013 ( 13 ), ten additional cases of LAMA5 -related recessive pediatric NS have been reported, with onset ages ranging from 3 months to 8 years, and various responses to treatment.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Case report: Genetic defects in laminin α5 cause infantile steroid-resistant nephrotic syndrome

et al. 2023

View full text Add to dashboard Cite

Single gene pathogenic mutations have been implicated in up to 30% of pediatric steroid-resistant nephrotic syndrome (SRNS) cases, mostly in infantile patients. Among them is LAMA5, which has been recently discovered and encodes the laminin α5 chain. The laminin α5β2γ1 heterotrimer is an essential component of the glomerular basement membrane and is necessary for embryogenesis and immune modulation. Biallelic LAMA5 variants have been identified in one adult and ten pediatric nephrotic syndromes (NS) patients with variable phenotypes. Biallelic truncating mutations in this gene have recently been proven to cause SRNS. Here, we present another case of infantile SRNS related to novel compound heterozygous variations of LAMA5 (c.3434G > A, p.Cys1145Tyr and c.6883C > T, p.Gln2295*), the first reported case with one missense and one nonsense allele. A 10-month-old female patient presented with eyelid edema and massive proteinuria without any extrarenal symptoms or family history. The patient was diagnosed with SRNS. Renal biopsy revealed focal segmental glomerulosclerosis with widely effaced epithelial foot processes and a “moth-eaten” appearance. She progressed to end stage kidney disease (ESKD), requiring dialysis at 31 months of age, and underwent a deceased-donor kidney transplant at 6 years of age. Four months after transplantation, she developed Ebstein-Barr Virus (EBV) infection related to post-transplantation lymphoproliferative disorder (PTLD). After chemotherapy, the patient remained healthy with adequate renal function without disease recurrence for the past 7 years. We also identified previous cases of biallelic LAMA5 variants associated with the nephrotic phenotype and analyzed the available clinical and genetic information. All reported patients had an onset of NS ranging from 3 months to 8 years, with no other syndromic features. Response to therapy and renal outcomes varied greatly; most patients exhibited steroid resistance, five progressed to ESKD, and two received kidney transplantation (KT). There was one report of PTLD. Our patient’s phenotype was markedly more severe than those with biallelic missense variants and somewhat less severe than those with two truncating variants. LAMA5 defects may also play a role in PTLD, though no conclusions can be made with such limited cases. LAMA5 should be considered a candidate gene for SRNS and should be actively tested in cases with no other genetic diagnosis.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Case report: Genetic defects in laminin α5 cause infantile steroid-resistant nephrotic syndrome

et al. 2023

View full text Add to dashboard Cite

show abstract

“…Although the mechanism of vinculin enhancement was unclear in our model animals, the expression of variant laminin α5 protein in this disease has effects on cell-matrix adhesions that differ from the effects in Lama5 -KO mice. Recently, Falcone et al reported new NS model mice with the homozygous Lama5 variant ( 11 ). Interestingly, their mice showed no obvious extrarenal phenotypes, although they also demonstrated decreased secretion of laminin α5 in GBM as in our KI mice.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, Falcone et al identified a homozygous mutation (E884G) in Lama5 by mouse phenotype-driven mutagenesis screening. The mice homozygous for the E884G Lama5 variant developed severe proteinuria ( 11 ). These lines of evidence in experiments using Lama5 gene-modified mice indicate that laminin α5 plays pivotal roles in GBM and lung BM.…”

Section: Introductionmentioning

confidence: 99%

A heterozygous LAMA5 variant may contribute to slowly progressive, vinculin-enhanced familial FSGS and pulmonary defects

Kaimori¹,

Kikkawa²,

Motooka³

et al. 2022

JCI Insight

View full text Add to dashboard Cite

The LAMA5 gene encodes laminin α5, an indispensable component of glomerular basement membrane and other types of basement membrane. A homozygous pathological variant in LAMA5 is known to cause systemic developmental syndrome, including glomerulopathy.However, the roles of heterozygous LAMA5 gene variants in human renal and systemic disease have remained unclear. We performed whole-exome sequence analyses of a family with slowly progressive nephropathy associated with hereditary focal segmental glomerulosclerosis; we identified a probable pathogenic novel variant of LAMA5, NP_005551.3:p.Val3687Met. In vitro analyses revealed cell type-dependent changes in secretion of variant laminin α5 LG4-5 domain. Heterozygous and homozygous knock-in mice with a corresponding variant of human LAMA5, p.Val3687Met, developed focal segmental glomerulosclerosis-like pathology with reduced laminin α5 and increased glomerular vinculin levels; this suggested that impaired cell adhesion may underlie this glomerulopathy. We also identified pulmonary defects such as bronchial deformity and alveolar dilation. Reexaminations of the family revealed phenotypes compatible with reduced laminin α5 and 4 increased vinculin levels in affected tissues. Thus, the heterozygous p.Val3687Met variant may cause a new syndromic nephropathy with focal segmental glomerulosclerosis through possibly defective secretion of laminin α5. Enhanced vinculin may be a useful disease marker.

show abstract

“…As lamininas são proteínas essenciais na formação da membrana basal glomerular, sendo formadas por heterotrímeros das cadeias α, β e γ. 177,237,238 Juntamente com as integrinas, as lamininas participam do cross-talk entre podócitos e MBG, contribuindo para a formação e manutenção da mesma. LAMA5 codifica a laminina α-5, subtipo predominante de cadeia alfa na forma madura da MBG.…”

Section: Discussionunclassified

Glomerulopatia colapsante idiopática: bases moleculares e correlações entre parâmetros moleculares, proteômicos, clínicos e histológicos

Neves

View full text Add to dashboard Cite

Dedico essa tese primeiramente a Deus, por me permitir alcançar sonhos que nunca pensei que fossem possíveis. Por zelar por mim e por todos que amo.Aos meus pais Anibal e Eliete, pela vida, amor incondicional, carinho e exemplo.Aos meus avós-pais Cecília e Jair Miranda (in memorian), pelos valores a mim ensinados e por moldarem a pessoa que hoje eu sou. O amor que tenho por vocês é infinito e infindável! Aos meus irmãos Karine, Isabela, Pedro, Gustavo e Ricardo por me fazerem entender o real sentido de fraternidade, pelo acolhimento, torcida e pelas bagunças.À minha esposa, Ramaiane Bridi, meu alicerce, maior incentivadora e grande amor da minha vida. Nada disso seria possível sem você ao meu lado. Amo muito você, minha polaca! Ao queridos Robson e Marilda, pelo acolhimento e receptividade.À minha família (avós, tios, primos, sobrinhos, afilhados, sogros e cunhados) por compreenderem a ausência frequente e por continuarem me apoiando e torcendo por mim em todas as etapas.Aos meus "filhos" Nino (in memorian) e Tufa, por me ensinarem que o amor, para ser sentido, não precisa ser traduzido em palavras. AgradecimentosAgradeço primeiramente aos pacientes que, de forma voluntária, aceitaram participar do estudo e sempre me incentivaram. Conheci muitas pessoas e histórias inspiradoras. Ao Prof. Dr. Luiz Fernando Onuchic, por ver em mim um potencial que eu não enxergava, por todas as oportunidades tanto na vida acadêmica quanto profissional, pelas longas conversas sobre a vida e por ser exemplo de caráter, retidão e rigor científico. Quisera o mundo fosse repleto de pessoas como o senhor. À Dra. Andréia Watanabe, querida amiga que esteve do meu lado desde a concepção do projeto, pela parceria e cumplicidade, ajuda inestimável e por todas as piadinhas que tornavam as exaustivas horas de experimento mais leves. Hi Bex!!! Ao Dr. Elieser Watanabe, amigo por quem tenho muito apreço, pela disponibilidade, insights científicos, auxílio em todas as fases do projeto, pelo exemplo de caráter e de médico. Ao Dr. Valkercyo Feitosa, médico brilhante e pessoa muito especial, por toda a ajuda, incentivo e parceria. Trabalhar com você foi uma honra e aprendizado imensuráveis. Aos amigos Drs. Jukelson e Lucas, pela amizade, apoio, discussões e por auxiliarem tão bem na condução da operação clínica do grupo de Nefropatias Hereditárias do HC-FMUSP Aos amigos do LIM29: Leandro, Fernanda, Vívian, Lívia Gilson, Jéssica, Eliene e Andressa, pelo companheirismo, carinho, ajuda, almoços no Burdog e pelo apoio irrestrito. Agradeço em especial à Talita por todo o carinho, cuidado e paciência nas análises proteômicas. Vocês com certeza fizeram com que tudo fosse mais fácil e sem vocês nada disse teria sido possível.

show abstract

A novel model of nephrotic syndrome results from a point mutation in Lama5 and is modified by genetic background

Cited by 6 publications

References 57 publications

Case report: Genetic defects in laminin α5 cause infantile steroid-resistant nephrotic syndrome

Case report: Genetic defects in laminin α5 cause infantile steroid-resistant nephrotic syndrome

A heterozygous LAMA5 variant may contribute to slowly progressive, vinculin-enhanced familial FSGS and pulmonary defects

Glomerulopatia colapsante idiopática: bases moleculares e correlações entre parâmetros moleculares, proteômicos, clínicos e histológicos

Contact Info

Product

Resources

About