# 615008

NEPHROTIC SYNDROME, TYPE 7; NPHS7


Alternative titles; symbols

NEPHROTIC SYNDROME, TYPE 7, WITH MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS


Other entities represented in this entry:

HEMOLYTIC UREMIC SYNDROME, ATYPICAL, SUSCEPTIBILITY TO, 7, INCLUDED; AHUS7, INCLUDED
AHUS, SUSCEPTIBILITY TO, 7, INCLUDED

Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
17q22 Nephrotic syndrome, type 7 615008 AR 3 DGKE 601440
17q22 {Hemolytic uremic syndrome, atypical, susceptibility to, 7} 615008 AR 3 DGKE 601440
Clinical Synopsis
 
Phenotypic Series
 

INHERITANCE
- Autosomal recessive
GENITOURINARY
Kidneys
- Hemolytic uremic syndrome (in some patients)
- Acute renal failure
- Nephrotic syndrome
- Proteinuria
- Membranoproliferative glomerulonephritis seen on biopsy
- Thickening of the glomerular basement membrane
- Splitting of the basement membrane
- Focal capillary obliteration
- Mesangial cell proliferation
- Effacement of podocyte foot processes
- Patchy deposition of IgG and IgM
- Subendothelial deposits
- Swelling of endothelial cells
- Chronic thrombotic microangiopathy
- End-stage renal failure (in some patients)
HEMATOLOGY
- Hemolytic anemia (in some patients)
- Thrombocytopenia (in some patients)
LABORATORY ABNORMALITIES
- Low serum albumin
- Normal serum complement levels
MISCELLANEOUS
- Onset usually in the first decade (range 0.8 to 5 years)
- Atypical hemolytic-uremic syndrome shows onset in first 12 months
- Progressive disorder
- Some patients may show response to immunosuppressive agents
- Some patients do not reach end-stage renal failure
MOLECULAR BASIS
- Caused by mutation in the diacylglycerol kinase, epsilon, 64-kD gene (DGKE, 601440.0001)
Hemolytic uremic syndrome - PS235400 - 11 Entries
Nephrotic syndrome - PS256300 - 26 Entries
Location Phenotype Inheritance Phenotype
mapping key
Phenotype
MIM number
Gene/Locus Gene/Locus
MIM number
1q23.1 Nephrotic syndrome, type 23 AR 3 619201 KIRREL1 607428
1q23.3 Nephrotic syndrome, type 22 AR 3 619155 NOS1AP 605551
1q25.2 Nephrotic syndrome, type 2 AR 3 600995 PDCN 604766
1q42.13 Nephrotic syndrome, type 18 AR 3 618177 NUP133 607613
3p21.31 Nephrotic syndrome, type 5, with or without ocular abnormalities AR 3 614199 LAMB2 150325
6p21.2 Nephrotic syndrome, type 24 AR 3 619263 DAAM2 606627
7q21.11 Nephrotic syndrome, type 15 AR 3 617609 MAGI2 606382
7q33 ?Nephrotic syndrome, type 13 AR 3 616893 NUP205 614352
10q22.1 RENI syndrome AR 3 617575 SGPL1 603729
10q23.33 Nephrotic syndrome, type 3 AR 3 610725 PLCE1 608414
11p13 Nephrotic syndrome, type 4 AD 3 256370 WT1 607102
11p11.2 ?Nephrotic syndrome, type 19 AR 3 618178 NUP160 607614
12p12.3 Nephrotic syndrome, type 6 AR 3 614196 PTPRO 600579
12q14.1 Nephrotic syndrome, type 21 AR 3 618594 AVIL 613397
12q15 Nephrotic syndrome, type 11 AR 3 616730 NUP107 607617
16p13.13 Nephrotic syndrome, type 10 AR 3 615861 EMP2 602334
16q13 Nephrotic syndrome, type 12 AR 3 616892 NUP93 614351
17q22 {Hemolytic uremic syndrome, atypical, susceptibility to, 7} AR 3 615008 DGKE 601440
17q22 Nephrotic syndrome, type 7 AR 3 615008 DGKE 601440
17q25.1 Nephrotic syndrome, type 17 AR 3 618176 NUP85 170285
17q25.3 Nephrotic syndrome, type 8 AR 3 615244 ARHGDIA 601925
19p13.2 Nephrotic syndrome, type 16 AR 3 617783 KANK2 614610
19q13.12 Nephrotic syndrome, type 1 AR 3 256300 NPHS1 602716
19q13.2 Nephrotic syndrome, type 9 AR 3 615573 COQ8B 615567
20q13.33 Nephrotic syndrome, type 26 AR 3 620049 LAMA5 601033
Xq22.3 Nephrotic syndrome, type 20 XL 3 301028 TBC1D8B 301027

TEXT

A number sign (#) is used with this entry because nephrotic syndrome type 7 (NPHS7) and susceptibility to atypical hemolytic uremic syndrome-7 (AHUS7) are caused by homozygous or compound heterozygous mutation in the DGKE gene (601440) on chromosome 17q22.


Description

Nephrotic syndrome type 7 is an autosomal recessive renal disease characterized by onset of nephrotic syndrome with proteinuria usually in the first decade of life. The disorder is progressive, and some patients develop end-stage renal disease within several years. Renal biopsy typically shows membranoproliferative glomerulonephritis. Some patients may benefit from immunosuppressive therapy (summary by Ozaltin et al., 2013).

Atypical hemolytic uremic syndrome-7 is characterized by acute onset in the first year of life of microangiopathic hemolytic anemia, thrombocytopenia, and renal failure. After the acute episode, most patients develop chronic renal insufficiency. Unlike other genetic forms of aHUS, AHUS7 is not related to abnormal activation of the complement system (summary by Lemaire et al., 2013).

For a general phenotypic description and a discussion of genetic heterogeneity of nephrotic syndrome, see NPHS1 (256300).

For a general phenotypic description and a discussion of genetic heterogeneity of aHUS, see AHUS1 (235400).


Clinical Features

Ozaltin et al. (2013) reported 9 patients from 3 unrelated consanguineous families with onset of progressive clinical nephrotic syndrome in early childhood. Renal biopsy in all cases showed glomerular injury with membranoproliferative glomerulonephritis (MPGN). Most had onset in the first 5 years of life, although 2 sibs in 1 family presented at ages 8 and 17 years. At onset, all had proteinuria and most had low serum albumin. In 1 family, the proband presented with nephrotic syndrome and renal insufficiency at age 2 years and died of meningitis a year later. His brother was the most severely affected patient: he developed end-stage renal failure at age 8 years and underwent renal transplant at age 20. Another affected sib developed end-stage renal disease at age 19 years, and the fourth had no end-stage renal disease at age 30. Treatment with immunosuppressive agents failed to induce remission in the patients in this family. Two sibs from a second family showed the mildest phenotype. The sisters developed nephrotic syndrome at ages 8 and 17 years. One developed end-stage renal failure at age 23 despite immunosuppressive treatment, whereas the other responded to immunosuppressive treatment and ACE inhibitors and did not have renal failure at age 19. In the third family, 3 sibs, including a pair of twins, presented with nephrotic syndrome at age 1.5 years, but none developed end-stage renal failure by ages 2 or 12 years. These 3 patients showed partial remission in response to immunosuppressive treatment. Renal biopsies in all patients were consistent with MPGN based on the findings of hypertrophic and hypercellular glomeruli, thickening of the basement membrane with focal capillary obliteration, endothelial cell swelling, splitting of the basement membrane, effacement of podocyte foot processes, and subendothelial deposits. There was some deposition of IgM and IgG, but no C3 (120700) deposition. Renal biopsy in the patient who presented at age 17 years showed some evidence of focal and segmental glomerulosclerosis (FSGS), a nonspecific finding in advanced glomerulopathy. Serum complement components C3 and C4 (see 120810) were normal in all individuals; serum CFH (134370) was not measured.

Lemaire et al. (2013) reported 13 patients from 9 unrelated families with onset of atypical hemolytic uremic syndrome within the first year of life. The infants presented with microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. Renal biopsies showed chronic thrombotic microangiopathy with glomerular hypercellularity, split basement membranes, and endothelial cell swelling without electron-dense deposits. Capillary lumens were narrowed, and there was evidence of effaced podocytes. The clinical course was characterized by relapsing episodes of aHUS before age 5 years. None of the patients had abnormalities of the complement system, and 2 patients treated with anticomplement therapy had relapses while on treatment. During follow-up, most patients developed chronic hypertension, microhematuria, and proteinuria, and 3 developed full nephrotic syndrome. Three patients received kidney transplant, none of whom had recurrence of aHUS. Twenty-two percent of sibs of index cases had aHUS, consistent with recessive transmission and high penetrance.


Inheritance

The transmission pattern of NPHS7 in the families reported by Ozaltin et al. (2013) was consistent with autosomal recessive inheritance.

The transmission pattern of AHUS7 in the families reported by Lemaire et al. (2013) was consistent with autosomal recessive inheritance.


Molecular Genetics

By homozygosity mapping combined with whole-exome analysis of a consanguineous family with early-onset nephrotic syndrome and MPGN, Ozaltin et al. (2013) identified a homozygous truncating mutation in the DGKE gene (Q43X; 601440.0001). Sequencing of this gene in 142 unrelated patients with a similar disorder identified 2 more consanguineous families with different homozygous truncating mutations (601440.0002 and 601440.0003). DGKE metabolizes and decreases intracellular DAG levels, thus contributing to the regulation of DAG levels. TRPC6 (603652) is a calcium-permeable cation channel expressed in the foot processes of podocytes and is known to be directly activated by DAG. In vitro functional expression studies in HEK293 cells showed that the DGKE mutants did not cause a decrease in TRPC6 current, as was observed with wildtype DGKE, consistent with a loss of DGKE function. The findings indicated that DGKE controls the intracellular concentration of DAG, which is a component of the phosphatidylinositol cycle that participates in multiple cellular functions and in lipid-mediated intracellular signaling. Perturbation of this pathway in podocytes may underlie the disorder.

In 13 patients from 9 families with early-onset atypical hemolytic-uremic syndrome, Lemaire et al. (2013) identified homozygous or compound heterozygous mutations in the DGKE gene (see, e.g., 601440.0004-601440.0008). The first mutations in 4 patients from 2 families were found by exome sequencing. Sequencing the DGKE gene in 47 additional unrelated probands with pediatric-onset aHUS and 36 adult-onset aHUS probands, in whom there was no mutation in known aHUS-associated genes or CFH antibodies, identified 6 additional pediatric index cases carrying rare homozygous or compound heterozygous DGKE variants. Another family with 3 affected individuals was identified independently. The mutations included 3 premature termination codons, 2 frameshift mutations, 1 splice site mutation, and 2 missense mutations that altered conserved residues. DGKE was a frequent cause of aHUS in the first year of life (13 (27%) of 49 cases with aHUS) and accounted for 50% of familial disease in this age group (3 of 6 kindreds). This uniformly early age of onset defined a distinct subgroup of aHUS. Renal biopsy of 1 patient showed no DGKE expression, suggesting that loss of DGKE function is the underlying mechanism. Lemaire et al. (2013) noted that DGKE phosphorylates and inactivates arachidonic acid-containing diacylglycerol (AA-DAG) to the corresponding phosphatidic acid. AA-DAG is the major signaling molecule that activates protein kinase C (PKC). PKC, in turn, increases the production of various prothrombotic factors in endothelial cells. Thus, loss of DGKE may result in sustained AA-DAG signaling, causing a prothrombotic state. In addition, DAGs modify slit diaphragm function in podocytes, a disturbance of which is consistent with renal-specific effects. The findings were important because this was the first genetic cause of aHUS not related to defects in genes encoding proteins in the complement cascade pathway.


REFERENCES

  1. Lemaire, M., Fremeaux-Bacchi, V., Schaefer, F., Choi, M., Tang, W. H., Le Quintrec, M., Fakhouri, F., Taque, S., Nobili, F., Martinez, F., Ji, W., Overton, J. D., and 18 others. Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome. Nature Genet. 45: 531-536, 2013. [PubMed: 23542698, images, related citations] [Full Text]

  2. Ozaltin, F., Li, B., Rauhauser, A., An, S.-W., Soylemezoglu, O., Gonul, I. I., Taskiran, E. Z., Ibsirlioglu, T., Korkmaz, E., Bilginer, Y., Duzova, A., Ozen, S., and 21 others. DGKE variants cause a glomerular microangiopathy that mimics membranoproliferative GN. J. Am. Soc. Nephrol. 24: 377-384, 2013. [PubMed: 23274426, images, related citations] [Full Text]


Contributors:
Cassandra L. Kniffin - updated : 5/31/2013
Creation Date:
Cassandra L. Kniffin : 1/8/2013
carol : 05/05/2016
carol : 6/3/2013
ckniffin : 5/31/2013
carol : 5/23/2013
carol : 3/14/2013
carol : 1/9/2013
ckniffin : 1/9/2013

# 615008

NEPHROTIC SYNDROME, TYPE 7; NPHS7


Alternative titles; symbols

NEPHROTIC SYNDROME, TYPE 7, WITH MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS


Other entities represented in this entry:

HEMOLYTIC UREMIC SYNDROME, ATYPICAL, SUSCEPTIBILITY TO, 7, INCLUDED; AHUS7, INCLUDED
AHUS, SUSCEPTIBILITY TO, 7, INCLUDED

ORPHA: 2134, 329903, 357008, 54370, 544472;   DO: 0080388;  


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
17q22 Nephrotic syndrome, type 7 615008 Autosomal recessive 3 DGKE 601440
17q22 {Hemolytic uremic syndrome, atypical, susceptibility to, 7} 615008 Autosomal recessive 3 DGKE 601440

TEXT

A number sign (#) is used with this entry because nephrotic syndrome type 7 (NPHS7) and susceptibility to atypical hemolytic uremic syndrome-7 (AHUS7) are caused by homozygous or compound heterozygous mutation in the DGKE gene (601440) on chromosome 17q22.


Description

Nephrotic syndrome type 7 is an autosomal recessive renal disease characterized by onset of nephrotic syndrome with proteinuria usually in the first decade of life. The disorder is progressive, and some patients develop end-stage renal disease within several years. Renal biopsy typically shows membranoproliferative glomerulonephritis. Some patients may benefit from immunosuppressive therapy (summary by Ozaltin et al., 2013).

Atypical hemolytic uremic syndrome-7 is characterized by acute onset in the first year of life of microangiopathic hemolytic anemia, thrombocytopenia, and renal failure. After the acute episode, most patients develop chronic renal insufficiency. Unlike other genetic forms of aHUS, AHUS7 is not related to abnormal activation of the complement system (summary by Lemaire et al., 2013).

For a general phenotypic description and a discussion of genetic heterogeneity of nephrotic syndrome, see NPHS1 (256300).

For a general phenotypic description and a discussion of genetic heterogeneity of aHUS, see AHUS1 (235400).


Clinical Features

Ozaltin et al. (2013) reported 9 patients from 3 unrelated consanguineous families with onset of progressive clinical nephrotic syndrome in early childhood. Renal biopsy in all cases showed glomerular injury with membranoproliferative glomerulonephritis (MPGN). Most had onset in the first 5 years of life, although 2 sibs in 1 family presented at ages 8 and 17 years. At onset, all had proteinuria and most had low serum albumin. In 1 family, the proband presented with nephrotic syndrome and renal insufficiency at age 2 years and died of meningitis a year later. His brother was the most severely affected patient: he developed end-stage renal failure at age 8 years and underwent renal transplant at age 20. Another affected sib developed end-stage renal disease at age 19 years, and the fourth had no end-stage renal disease at age 30. Treatment with immunosuppressive agents failed to induce remission in the patients in this family. Two sibs from a second family showed the mildest phenotype. The sisters developed nephrotic syndrome at ages 8 and 17 years. One developed end-stage renal failure at age 23 despite immunosuppressive treatment, whereas the other responded to immunosuppressive treatment and ACE inhibitors and did not have renal failure at age 19. In the third family, 3 sibs, including a pair of twins, presented with nephrotic syndrome at age 1.5 years, but none developed end-stage renal failure by ages 2 or 12 years. These 3 patients showed partial remission in response to immunosuppressive treatment. Renal biopsies in all patients were consistent with MPGN based on the findings of hypertrophic and hypercellular glomeruli, thickening of the basement membrane with focal capillary obliteration, endothelial cell swelling, splitting of the basement membrane, effacement of podocyte foot processes, and subendothelial deposits. There was some deposition of IgM and IgG, but no C3 (120700) deposition. Renal biopsy in the patient who presented at age 17 years showed some evidence of focal and segmental glomerulosclerosis (FSGS), a nonspecific finding in advanced glomerulopathy. Serum complement components C3 and C4 (see 120810) were normal in all individuals; serum CFH (134370) was not measured.

Lemaire et al. (2013) reported 13 patients from 9 unrelated families with onset of atypical hemolytic uremic syndrome within the first year of life. The infants presented with microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. Renal biopsies showed chronic thrombotic microangiopathy with glomerular hypercellularity, split basement membranes, and endothelial cell swelling without electron-dense deposits. Capillary lumens were narrowed, and there was evidence of effaced podocytes. The clinical course was characterized by relapsing episodes of aHUS before age 5 years. None of the patients had abnormalities of the complement system, and 2 patients treated with anticomplement therapy had relapses while on treatment. During follow-up, most patients developed chronic hypertension, microhematuria, and proteinuria, and 3 developed full nephrotic syndrome. Three patients received kidney transplant, none of whom had recurrence of aHUS. Twenty-two percent of sibs of index cases had aHUS, consistent with recessive transmission and high penetrance.


Inheritance

The transmission pattern of NPHS7 in the families reported by Ozaltin et al. (2013) was consistent with autosomal recessive inheritance.

The transmission pattern of AHUS7 in the families reported by Lemaire et al. (2013) was consistent with autosomal recessive inheritance.


Molecular Genetics

By homozygosity mapping combined with whole-exome analysis of a consanguineous family with early-onset nephrotic syndrome and MPGN, Ozaltin et al. (2013) identified a homozygous truncating mutation in the DGKE gene (Q43X; 601440.0001). Sequencing of this gene in 142 unrelated patients with a similar disorder identified 2 more consanguineous families with different homozygous truncating mutations (601440.0002 and 601440.0003). DGKE metabolizes and decreases intracellular DAG levels, thus contributing to the regulation of DAG levels. TRPC6 (603652) is a calcium-permeable cation channel expressed in the foot processes of podocytes and is known to be directly activated by DAG. In vitro functional expression studies in HEK293 cells showed that the DGKE mutants did not cause a decrease in TRPC6 current, as was observed with wildtype DGKE, consistent with a loss of DGKE function. The findings indicated that DGKE controls the intracellular concentration of DAG, which is a component of the phosphatidylinositol cycle that participates in multiple cellular functions and in lipid-mediated intracellular signaling. Perturbation of this pathway in podocytes may underlie the disorder.

In 13 patients from 9 families with early-onset atypical hemolytic-uremic syndrome, Lemaire et al. (2013) identified homozygous or compound heterozygous mutations in the DGKE gene (see, e.g., 601440.0004-601440.0008). The first mutations in 4 patients from 2 families were found by exome sequencing. Sequencing the DGKE gene in 47 additional unrelated probands with pediatric-onset aHUS and 36 adult-onset aHUS probands, in whom there was no mutation in known aHUS-associated genes or CFH antibodies, identified 6 additional pediatric index cases carrying rare homozygous or compound heterozygous DGKE variants. Another family with 3 affected individuals was identified independently. The mutations included 3 premature termination codons, 2 frameshift mutations, 1 splice site mutation, and 2 missense mutations that altered conserved residues. DGKE was a frequent cause of aHUS in the first year of life (13 (27%) of 49 cases with aHUS) and accounted for 50% of familial disease in this age group (3 of 6 kindreds). This uniformly early age of onset defined a distinct subgroup of aHUS. Renal biopsy of 1 patient showed no DGKE expression, suggesting that loss of DGKE function is the underlying mechanism. Lemaire et al. (2013) noted that DGKE phosphorylates and inactivates arachidonic acid-containing diacylglycerol (AA-DAG) to the corresponding phosphatidic acid. AA-DAG is the major signaling molecule that activates protein kinase C (PKC). PKC, in turn, increases the production of various prothrombotic factors in endothelial cells. Thus, loss of DGKE may result in sustained AA-DAG signaling, causing a prothrombotic state. In addition, DAGs modify slit diaphragm function in podocytes, a disturbance of which is consistent with renal-specific effects. The findings were important because this was the first genetic cause of aHUS not related to defects in genes encoding proteins in the complement cascade pathway.


REFERENCES

  1. Lemaire, M., Fremeaux-Bacchi, V., Schaefer, F., Choi, M., Tang, W. H., Le Quintrec, M., Fakhouri, F., Taque, S., Nobili, F., Martinez, F., Ji, W., Overton, J. D., and 18 others. Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome. Nature Genet. 45: 531-536, 2013. [PubMed: 23542698] [Full Text: https://doi.org/10.1038/ng.2590]

  2. Ozaltin, F., Li, B., Rauhauser, A., An, S.-W., Soylemezoglu, O., Gonul, I. I., Taskiran, E. Z., Ibsirlioglu, T., Korkmaz, E., Bilginer, Y., Duzova, A., Ozen, S., and 21 others. DGKE variants cause a glomerular microangiopathy that mimics membranoproliferative GN. J. Am. Soc. Nephrol. 24: 377-384, 2013. [PubMed: 23274426] [Full Text: https://doi.org/10.1681/ASN.2012090903]


Contributors:
Cassandra L. Kniffin - updated : 5/31/2013

Creation Date:
Cassandra L. Kniffin : 1/8/2013

Edit History:
carol : 05/05/2016
carol : 6/3/2013
ckniffin : 5/31/2013
carol : 5/23/2013
carol : 3/14/2013
carol : 1/9/2013
ckniffin : 1/9/2013