Monogenic causes of steroid-resistant nephrotic syndrome

Gene	Gene product or protein	Kidney histology	Additional notes or associated extrarenal features	OMIM phenotype
Autosomal recessive
NPHS1	Nephrin	FSGS		#256300
NPHS2	Podocin	FSGS		#600995
PLCE1	Phospholipase C, epsilon1	FSGS or DMS		#610725
CD2AP	CD2-associated protein	FSGS		#607832
PTPRO	Protein-tyrosine phosphatase receptor-type O (or glomerular epithelial protein 1/GLEPP1)	FSGS		#614196
DGKE	Diacylglycerol kinase-epsilon	MPGN^[1]	Atypical hemolytic uremic syndrome	#615008
EMP2	Epithelial membrane protein-2, which regulates caveolin-1 in kidney	n/a	Few case reports^[2]	#615861
MYO1E	Myosin 1E	FSGS		#614131
TTC21B	Intraflagellar transport protein 139	FSGS	Ciliary dysfunction; causes nephronophthisis	#613820
CRB2	Crumbs homolog 2 protein	FSGS, congenital nephrotic syndrome	Renal microcysts and cerebral ventriculomegaly	#616220
CUBN	Cubilin	Renal histology not described	Might be associated with megaloblastic anemia, because cubilin facilitates intestinal absorption of the vitamin B12 or intrinsic factor complex	#618884 #261100
MAGI2	Membrane-associated guanylate kinase; multiprotein complex associated with podocytes	FSGS	Congenital nephrotic syndrome^[3]	#617609
NUP85 NUP93 NUP107 NUP133 NUP160 NUP205 XP05	Nuclear pore complex: nucleoporins 85 kDa, 93 kDa, 107 kDa, 133 kDa, 160 kDa, 205 kDa, and nuclear export protein exportin 5 (interacts with nucleoporins)	FSGS or DMS	Nucleoporins mediate transport of proteins or RNA from cell cytoplasm to nucleus. SRNS with ESRD in childhood^[4,5]; might have partial response to cyclosporine.	#618176 #616892 #616730 #618177 #618178 #616893
Autosomal dominant
ACTN4	Actinin-alpha-4	FSGS		#603278
TRPC6	Transient receptor potential cation channel, subfamily C, member 6	FSGS		#603965
INF2	Inverted formin 2	FSGS	Variants in INF2 also may cause a form of Charcot-Marie-Tooth disease	#613237
ARHGAP24	Rho-GTPase-activating protein 24	FSGS
ANLN	Anillin	FSGS	Childhood or adult onset	#616032
PAX2	Paired box protein 2	FSGS	May include renal hypoplasia and optic nerve coloboma	#636002 #120330
Syndromic forms of nephrotic syndrome
WT1 (AD)	Wilms tumor protein	Denys-Drash syndrome – DMS	Early nephrotic syndrome with diffuse mesangial sclerosis; 46XY children have gonadal dysgenesis and atypical or female-appearing external genitalia (male pseudohermaphroditism), Wilms tumor, gonadoblastoma	#194080
		Frasier syndrome – FSGS	SRNS; 46XY children have gonadal dysgenesis and atypical or female-appearing external genitalia (male pseudohermaphroditism), gonadoblastoma risk	#136680
		Nephrotic syndrome – FSGS		#256370
LAMB2 (AR)	Laminin subunit beta-2	DMS	Pierson syndrome – Congenital nephrotic syndrome, DMS, microcoria and buphthalmos, severe neurodevelopmental delay	#614199
LMX1B (AD)	LIM homeobox transcription factor 1-beta	FSGS	Nail-patella syndrome – Absent or displaced patella, absent or pitted nails, small nails, hematuria, proteinuria, nephrotic syndrome in 10 to 15% (SRNS)	#256020
SMARCAL1 (AR)	Swi/Snf-related matrix-associated actin-dependent regulator of chromatin subfamily A-like protein	FSGS	Schimke immuno-osseous dysplasia – Short stature, spondyloepiphyseal dysplasia, SRNS, kidney failure, T cell immunodeficiency, lentigines, abnormal dentition, thin hair, corneal opacities, arteriosclerosis, headache, cerebral infarcts	#242900
SCARB2 (AR)	Scavenger receptor class B member 2	FSGS	Action myoclonus-renal failure syndrome – FSGS, kidney failure, fine tremor, progressive myoclonus epilepsy	#254900
WDR73 (AR)	WD repeat containing protein 73	FSGS (collapsing) or DMS	Galloway-Mowat syndrome – Microcephaly, gyral abnormalities (polymicrogyria), hypotonia, seizures, developmental delay, hiatus hernia, kidney failure	#251300
MYH9 (AD)	Nonmuscle myosin heavy-chain IIA	FSGS	May-Hegglin – Giant platelets, thrombocytopenia Fechtner – Sensorineural deafness, cataracts, giant platelets, thrombocytopenia, kidney failure in 28% Epstein – Sensorineural deafness, giant platelets, thrombocytopenia, nephritis	#155100
ITGA3 (AR)	Integrin alpha-3 subunit	FSGS	Interstitial lung disease, epidermolysis bullosa	#614748
ARHGDIA	Rho-GDP dissociation inhibitor alpha	DMS	Intellectual disability	#615244
SGPL1	Sphingosine-1-phosphate lyase-1	FSGS	RENI syndrome – Primary adrenal insufficiency, cryptorchidism, hypothyroidism, neurologic symptoms^[6]	#617575
INF2 (AD)	Inverted formin 2	FSGS	Charcot-Marie-Tooth – Neuropathy and deafness	#614455
Mitochondrial podocytopathies
COQ8B	aarF domain-containing kinase 4	FSGS (collapsing)	CoQ10 deficiency	#615573
COQ6	Coenzyme Q10 biosynthesis mono-oxygenase 6	FSGS or DMS	Seizures and sensorineural deafness	#614650
COQ2	Coenzyme Q10 biosynthesis mono-oxygenase 2	FSGS	Seizures, hypotonia, lactic acidosis, encephalomyopathy	#607426
MTTL1	Mitochondrial tRNA^Leu(UUR)	FSGS	MELAS – Myopathy, encephalopathy, lactic acidosis, stroke-like episode Some individuals have diabetes and deafness	#540000
PDSS2	Decaprenyl diphosphate synthase subunit 2	Renal histology not described	Growth retardation, ataxia, deafness	#614652

This table lists most of the genes that have been associated with SRNS. A few other genes have been identified in case reports; a full list of the genetic heterogeneity of nephrotic syndrome is available on the MIM website.

DMS: diffuse mesangial sclerosis; ESRD: end-stage renal disease; FSGS: focal segmental glomerulosclerosis; n/a: not available; MPGN: membranoproliferative glomerulonephritis; RENI: renal, endocrine, neurologic, and immune syndrome; RNA: ribonucleic acid; SRNS: steroid-resistant nephrotic syndrome.

Original figure modified for this publication. Reproduced from: Noone DG, Iijima K, Parekh R. Idiopathic nephrotic syndrome in children. Lancet 2018; 392:61. Table used with the permission of Elsevier Inc. All rights reserved.

References:

Ozaltin F, Li B, Rauhauser A, et al. DGKE variants cause a glomerular microangiopathy that mimics membranoproliferative GN. J Am Soc Nephrol 2013; 24:377.
Gee HY, Ashraf S, Wan X, et al. Mutations in EMP2 cause childhood-onset nephrotic syndrome. Am J Hum Genet 2014; 94:884.
Bierzynska A, Soderquest K, Dean P, et al. MAGI2 mutations cause congenital nephrotic syndrome. J Am Soc Nephrol 2017; 28:1614.
Braun DA, Sadowski CE, Kohl S, et al. Mutations in nuclear pore genes NUP93, NUP205 and XPO5 cause steroid-resistant nephrotic syndrome. Nat Genet 2016; 48:457.
Braun DA, Lovric S, Schapiro D, et al. Mutations in multiple components of the nuclear pore complex cause nephrotic syndrome. J Clin Invest 2018; 128:4313.
Lovric S, Goncalves S, Gee HY, et al. Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency. J Clin Invest 2017; 127:912.

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Monogenic causes of steroid-resistant nephrotic syndrome