G2Cdb::Human Disease report

Disease id
D00000267
Name
Focal segmental glomerulosclerosis
Nervous system disease
no

Genes (1)

Gene Name/Description Mutations Found Literature Mutations Type Genetic association?
G00001793 ACTN4
actinin, alpha 4
Y (16251236) Single nucleotide polymorphism (SNP) Y
G00001793 ACTN4
actinin, alpha 4
Y (16251236) Single nucleotide deletion (SND) Y
G00001793 ACTN4
actinin, alpha 4
Y (15627790) Single nucleotide polymorphism (SNP) N

References

  • Mutational and Biological Analysis of alpha-actinin-4 in focal segmental glomerulosclerosis.

    Weins A, Kenlan P, Herbert S, Le TC, Villegas I, Kaplan BS, Appel GB and Pollak MR

    Renal Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.

    Mutations in the alpha-actinin-4 gene (ACTN4) cause an autosomal dominant form of focal segmental glomerulosclerosis (FSGS). A mutational analysis was performed of ACTN4 in DNA from probands with a family history of FSGS as well as in individuals with nonfamilial FSGS. The possible contribution of noncoding variation in ACTN4 to the development of FSGS also was assessed. Multiple nucleotide variants were identified in coding and noncoding sequence. The segregation of nonsynonymous coding sequence variants was examined in the relevant families. Only a small number of nucleotide changes that seemed likely to be causing (or contributing to) disease were identified. Sequence changes that predicted I149del, W59R, V801M, R348Q, R837Q, and R310Q changes were identified. For studying their biologic relevance and their potential roles in the pathogenesis of FSGS, these variants were expressed as GFP-fusion proteins in cultured podocytes. F-actin binding assays also were performed. Three of these variants (W59R, I149del, and V801M) showed clear cellular mislocalization in the form of aggregates adjacent to the nucleus. Two of these mislocalized variants (W59R and I149del) also showed an increased actin-binding activity. The I149del mutation segregated with disease; W59R was found to be a de novo mutation in the proband. A total of five ACTN4 mutations that are believed to be disease causing (three reported previously and two novel) as well as a number of variants with unclear contribution to disease now have been identified. The possibility that some of these other variants increase the susceptibility to FSGS cannot be excluded. ACTN4 mutations seem to account for approximately 4% of familial FSGS.

    Funded by: NIDDK NIH HHS: DK54931, DK59588

    Journal of the American Society of Nephrology : JASN 2005;16;12;3694-701

  • Molecular analysis of NPHS2 and ACTN4 genes in a series of 33 Italian patients affected by adult-onset nonfamilial focal segmental glomerulosclerosis.

    Aucella F, De Bonis P, Gatta G, Muscarella LA, Vigilante M, di Giorgio G, D'Errico M, Zelante L, Stallone C and Bisceglia L

    Department of Nephrology and Dialysis, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo, Italy.

    Background: Mutations in the NPHS2 gene, encoding podocin, and in the ACTN4 gene, encoding alpha-actinin-4, have been identified in familial childhood-onset forms of focal and segmental glomerulosclerosis (FSGS). NPHS2 may be also responsible for some sporadic cases. The role of NPHS2 and ACTN4 in the adult sporadic form of the disease is being clarifying.

    Methods: Thirty-three adult subjects affected by sporadic FSGS were studied at molecular level. At biopsy, 12 patients had nephrotic syndrome, 5 patients had isolated proteinuria and 16 patients showed proteinuria and hematuria. Glomerular filtration rate (GFR) was in the normal range in 19 subjects and 14 patients had a variable degree of renal failure. Multiplex families presenting with a clear familial inheritance for proteinuria or other congenital nephrotic syndrome were excluded. The whole coding region, all intron/exon boundaries and flanking intronic regions of NPHS2 gene and the exon 8, i.e. hot-spot mutations of the ACTN4 gene, were analyzed in all patients by denaturing high-performance liquid chromatography (DHPLC) to search disease-causing defects.

    Results: The analysis identified four already described and two new polymorphisms, IVS3-21C>T and IVS3-46C>T, on the NPHS2 gene. Moreover, the R229Q allele was identified in 3/33 patients and in 7/124 controls, accounting for an allelic frequency of 0.045 and 0.028, respectively. The new intronic polymorphism IVS7-54C>T was also found in the exon 8 of the ACTN4 gene.

    Conclusions: In this study, we exhaustively analyzed the NPHS2 and the exon 8 of the ACTN4 genes in a series of sporadic 'adult-onset' FSGS patients. No causative mutations were found while the R229Q allele was identified in 3 patients confirming its possible role as a 'disease-associated NPHS2 allele' although its pathogenetic involvement needs to be further clarified. Moreover, the description of new intronic polymorphisms in both genes is reported.

    Nephron. Clinical practice 2005;99;2;c31-6

Literature (2)

Pubmed - human_disease

  • Molecular analysis of NPHS2 and ACTN4 genes in a series of 33 Italian patients affected by adult-onset nonfamilial focal segmental glomerulosclerosis.

    Aucella F, De Bonis P, Gatta G, Muscarella LA, Vigilante M, di Giorgio G, D'Errico M, Zelante L, Stallone C and Bisceglia L

    Department of Nephrology and Dialysis, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo, Italy.

    Background: Mutations in the NPHS2 gene, encoding podocin, and in the ACTN4 gene, encoding alpha-actinin-4, have been identified in familial childhood-onset forms of focal and segmental glomerulosclerosis (FSGS). NPHS2 may be also responsible for some sporadic cases. The role of NPHS2 and ACTN4 in the adult sporadic form of the disease is being clarifying.

    Methods: Thirty-three adult subjects affected by sporadic FSGS were studied at molecular level. At biopsy, 12 patients had nephrotic syndrome, 5 patients had isolated proteinuria and 16 patients showed proteinuria and hematuria. Glomerular filtration rate (GFR) was in the normal range in 19 subjects and 14 patients had a variable degree of renal failure. Multiplex families presenting with a clear familial inheritance for proteinuria or other congenital nephrotic syndrome were excluded. The whole coding region, all intron/exon boundaries and flanking intronic regions of NPHS2 gene and the exon 8, i.e. hot-spot mutations of the ACTN4 gene, were analyzed in all patients by denaturing high-performance liquid chromatography (DHPLC) to search disease-causing defects.

    Results: The analysis identified four already described and two new polymorphisms, IVS3-21C>T and IVS3-46C>T, on the NPHS2 gene. Moreover, the R229Q allele was identified in 3/33 patients and in 7/124 controls, accounting for an allelic frequency of 0.045 and 0.028, respectively. The new intronic polymorphism IVS7-54C>T was also found in the exon 8 of the ACTN4 gene.

    Conclusions: In this study, we exhaustively analyzed the NPHS2 and the exon 8 of the ACTN4 genes in a series of sporadic 'adult-onset' FSGS patients. No causative mutations were found while the R229Q allele was identified in 3 patients confirming its possible role as a 'disease-associated NPHS2 allele' although its pathogenetic involvement needs to be further clarified. Moreover, the description of new intronic polymorphisms in both genes is reported.

    Nephron. Clinical practice 2005;99;2;c31-6

Pubmed - other

  • Mutational and Biological Analysis of alpha-actinin-4 in focal segmental glomerulosclerosis.

    Weins A, Kenlan P, Herbert S, Le TC, Villegas I, Kaplan BS, Appel GB and Pollak MR

    Renal Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.

    Mutations in the alpha-actinin-4 gene (ACTN4) cause an autosomal dominant form of focal segmental glomerulosclerosis (FSGS). A mutational analysis was performed of ACTN4 in DNA from probands with a family history of FSGS as well as in individuals with nonfamilial FSGS. The possible contribution of noncoding variation in ACTN4 to the development of FSGS also was assessed. Multiple nucleotide variants were identified in coding and noncoding sequence. The segregation of nonsynonymous coding sequence variants was examined in the relevant families. Only a small number of nucleotide changes that seemed likely to be causing (or contributing to) disease were identified. Sequence changes that predicted I149del, W59R, V801M, R348Q, R837Q, and R310Q changes were identified. For studying their biologic relevance and their potential roles in the pathogenesis of FSGS, these variants were expressed as GFP-fusion proteins in cultured podocytes. F-actin binding assays also were performed. Three of these variants (W59R, I149del, and V801M) showed clear cellular mislocalization in the form of aggregates adjacent to the nucleus. Two of these mislocalized variants (W59R and I149del) also showed an increased actin-binding activity. The I149del mutation segregated with disease; W59R was found to be a de novo mutation in the proband. A total of five ACTN4 mutations that are believed to be disease causing (three reported previously and two novel) as well as a number of variants with unclear contribution to disease now have been identified. The possibility that some of these other variants increase the susceptibility to FSGS cannot be excluded. ACTN4 mutations seem to account for approximately 4% of familial FSGS.

    Funded by: NIDDK NIH HHS: DK54931, DK59588

    Journal of the American Society of Nephrology : JASN 2005;16;12;3694-701

© G2C 2014. The Genes to Cognition Programme received funding from The Wellcome Trust and the EU FP7 Framework Programmes:
EUROSPIN (FP7-HEALTH-241498), SynSys (FP7-HEALTH-242167) and GENCODYS (FP7-HEALTH-241995).

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