The podocin V260E mutation predicts steroid resistant nephrotic syndrome in black South African children with focal segmental glomerulosclerosis

Abstract

In black African children with focal segmental glomerulosclerosis (FSGS) there are high rates of steroid resistance. The aim was to determine genetic associations with apolipoprotein L1 (APOL1) renal risk variants and podocin (NPHS2) variants in 30 unrelated black South African children with FSGS. Three APOL1 variants were genotyped and the exons of the NPHS2 gene sequenced in the cases and controls. APOL1 risk alleles show a modest association with steroid sensitive nephrotic syndrome (SSNS) and steroid resistant nephrotic syndrome (SRNS). The NPHS2 V260E variant was present in SRNS cases (V/V = 5; V/E = 4; E/E = 11), and was absent in SSNS cases. Haplotype analysis suggests a single mutation origin for V260E and it was associated with a decline in kidney function over a 60-month period (p = 0.026). The V260E variant is a good predictor of autosomal recessive SRNS in black South African children and could provide useful information in a clinical setting.

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“…As expected (Eddy & Symons, 2003), the children with SRNS were significantly older at presentation, otherwise the groups were demographically similar. Genetics are known to play a role in steroid-responsiveness (Adeyemo et al, 2018;Asharam et al, 2018;Govender et al, 2019;Gribouval et al, 2018Gribouval et al, , 2019. However, while genetic and other mechanisms underlying steroid-responsiveness in this small cohort were not evaluated in the present study, they have been the subject of previously reported biomarker studies (Agrawal et al, 2020;Gooding et al, 2020).…”

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“…Nephrotic syndrome varies in histological pattern, steroid response and long-term outcomes by race, ethnicity and geography, reflecting in part differences in the prevalence of underlying common and rare genetic variants predisposing or causing nephrotic syndrome, respectively. (38,42,(59)(60)(61)(62)(63)(64)(65)(66) Primary nephrotic syndrome in children is classified by response to corticosteroid therapy, pattern of relapse, histopathology and the presence or absence of causative genetic mutations. (67) The majority of patients are steroid sensitive, but approximately 10%-20% are steroid-resistant (SRNS) and are at a significantly greater risk of developing ESKD, with 50%-70% of children developing ESKD within 5-10 years of diagnosis.…”

“…Tsonga, Tswana, Swati, Sotho, Pedi and Zulu) of the Bantu ancestry, suggesting that the variant may be broadly distributed in Southern Africa. (65,66) NPHS2 encodes podocin, a critical protein required for the integrity of the podocyte slit diaphragm, as an essential component of the tripartite glomerular filtration barrier. The p.V260E mutation, previously reported in consanguineous families in the former Omani empire, disrupts the transport of the protein from the endoplasmic reticulum to the plasma membrane.…”

“…In two studies enrolling children <18 years of age with SRNS, NPHS2 homozygosity for NPHS2 p.V260E provided a precision molecular diagnosis in 33% and 55% of children with SR-FSGS. (65,66) Age-of-onset for p.V260E homozygotes ranged from less than 2 to 12 years of age. (65,66) Although neither African study assessed children with congenital nephrotic syndrome, previous studies have reported five congenital cases (age-of-onset in the first 3 months of age) homozygous for p.V260E from the Comoros Island and Saudi Arabia.…”

“…(65,66) Age-of-onset for p.V260E homozygotes ranged from less than 2 to 12 years of age. (65,66) Although neither African study assessed children with congenital nephrotic syndrome, previous studies have reported five congenital cases (age-of-onset in the first 3 months of age) homozygous for p.V260E from the Comoros Island and Saudi Arabia. (77,78) This variable age-of-onset is also seen within families with affected siblings developing SR-FSGS at 3 and 10 years in one family and 6 and 9 years in a second family.…”