Individuals with TBMN and R229Q are carriers of the autosomal recessive forms of both Alport syndrome and familial focal segmental glomerulosclerosis (FSGS).
We calculated crude odds ratios and 95% confidence intervals of childhood nephrotic syndrome and focal segmental glomerulosclerosis associated with R229Q heterozygosity using data from five studies.
A family with three members homozygous for the NPHS2 p.R229Q variant is presented: a 37-year-old patient who was diagnosed with proteinuria at age 7 months, focal segmental glomerulosclerosis (FSGS) at age 20 years, and end-stage renal disease (ESRD) at age 33 years, his 59 year-old father and his 40 year-old brother, both unaffected with no proteinuria.
Individuals with TBMN and R229Q are carriers of the autosomal recessive forms of both Alport syndrome and familial focal segmental glomerulosclerosis (FSGS).
To further define the implication of R229Q, a familial case was characterized with two nephrotic siblings presenting the association of the R229Q with A297V mutation that were inherited from healthy mother and father, respectively.
Identification of R229Q mutations may be of clinical importance, as NPHS2-associated disease appears to define a subgroup of FSGS patients unresponsive to corticosteroids.
In conclusion, our meta-analysis suggests that for adult-onset disease (onset age > 18), the homozygous variant could be a potential predictor of hereditary nephrotic syndrome and that the p.R229Q allele cannot currently be considered a risk factor for predicting FSGS.
Individuals with TBMN and R229Q are carriers of the autosomal recessive forms of both Alport syndrome and familial focal segmental glomerulosclerosis (FSGS).
The common variant R229Q of podocin, recently associated with late-onset focal segmental glomerulosclerosis, had an overall allelic frequency of 4.2% versus 2.5% in controls.
In this paper, we present the currently known pathogenic and benign associations, and show that a rare p.R229Q association can be considered pathogenic if the variant in trans meets the following criteria; it affects the 270-351 residues and alters but does not disrupt the oligomerization, its p.R229Q association is found in a family with slowly progressing focal segmental glomerulosclerosis, but is expected to be rare in the general population (<1:10<sup>6</sup> ).
The podocin mutation R229Q may play a role in the pathogenesis of FSGS and in early recurrence after transplantation, but does not allow accurate prediction of recurrence or the associated potential for prevention.
To date, very few cases with adult-onset focal segmental glomerulosclerosis (FSGS) carrying NPHS2 variants have been described, all of them being compound heterozygous for the p.R229Q variant and one pathogenic mutation.
A compound heterozygous podocin mutation was identified in our FSGS patient, leading to a truncated (podocin (V165X)) and a missense mutant protein (podocin (R168H)), respectively.
R138Q carriers were more frequent among FSGS cases relative to controls (OR = 4.9, P = 0.06), but heterozygosity for the other four missense mutations was equally distributed among FSGS cases and controls.
The prevalence of p.P20L polymorphism was not significantly different among the groups (6 % in FSGS patients, 1.8 % in IGAN patients, 1 % in the control group).
Eight of these (p.R138Q, p.V180M, p.R229Q, p.E237Q, p.A242V, p.A284V, p.L327F and the frameshift 855-856 delAA) are alleles previously reported to cause FSGS in either the homozygous or compound heterozygous states, while the remaining 7 (p.R10T, p.V127W, p.Q215X, p.T232I, p.L270F, p.L312V and the frameshift 397delA) are novel alleles that have not been demonstrated previously.
Eight of these (p.R138Q, p.V180M, p.R229Q, p.E237Q, p.A242V, p.A284V, p.L327F and the frameshift 855-856 delAA) are alleles previously reported to cause FSGS in either the homozygous or compound heterozygous states, while the remaining 7 (p.R10T, p.V127W, p.Q215X, p.T232I, p.L270F, p.L312V and the frameshift 397delA) are novel alleles that have not been demonstrated previously.
A compound heterozygous podocin mutation was identified in our FSGS patient, leading to a truncated (podocin (V165X)) and a missense mutant protein (podocin (R168H)), respectively.
The prevalence of p.P20L polymorphism was not significantly different among the groups (6 % in FSGS patients, 1.8 % in IGAN patients, 1 % in the control group).
The second, a 31-year-old woman-compound heterozygous for p.V290M and p.R138Q-was first detected with hypoalbuminemia (<30 g/l) and edema at the age of 24.3 and 27.5 years, respectively.