Irregular glomerular basement membrane thickening with foci of splitting of the lamina densa - USMLE Forums
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Old 01-16-2012
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Kidney Irregular glomerular basement membrane thickening with foci of splitting of the lamina densa

A 23-year-old female presented with progressive renal illness since childhood. She gave history of recurrent episodes of oedema of the face and feet. For the last 2 years she had attacks of gross haema*turia. A renal biopsy done 5 years earlier showed diffuse mesangial proliferation with focal thickening as well as irregular glomerular basement membrane thickening with foci of splitting of the lamina densa. Her only brother had died of chronic renal disease at the age of seventeen. Her biochemical workup revealed increased blood urea (123 mg/dl) and serum creatinine (8.7 mg/dl). There was borderline hypo*natremia and hypokalemia. Urine examination showed proteinuria and microscopic haematuria. Her visual acuity was 6/60 in both eyes with mild cataracts. What is the cause of her condition?
A) Mutation at the gene for the α5 chain of type IV collagen
B) Mutation in the INF2
C) Mutation in the PKD1
D) Mutation in the PKD2
E) mutation in the TRPC6

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Old 01-16-2012
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Its pkd1 on chr 16
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Old 01-16-2012
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Ans A = Alport syndrome , = splitting of basement membrane + associated with ocular and hearing abnormality .
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Old 01-16-2012
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A) Mutation at the gene for the α5 chain of type IV collagen
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Old 07-05-2012
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Alport's disease is an X-linked condition so males should be affected
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Old 07-05-2012
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This seems to be a case of familial focal segmental glomerulosclerosis.
According to Wikipedia:
There are currently several known genetic causes of the hereditary forms of FSGS.
TRPC6, which encodes a member of the family of TRP channels. This family of ion channels conduct cations in a largely non-selective manner.TRPC6 is expressed in podocytes. TRPC6 is known to be activated by phospholipase C stimulation. There are at least 6 mutations in this channel, located throughout the channel. At least one of these mutations, P112Q, leads to increased intracellular calcium influx. It is unclear how this might lead to FSGS, though it has been proposed that it may result in alteration of podocyte dynamics or podocytopenia.[7]
FSGS1:
ACTN4603278The first gene involved with this disorder is ACTN4, which encodes alpha-actinin 4. This protein crosslinks bundles of actin filaments and is present in the podocyte. Mutations in this protein associated with FSGS result in increased affinity for actin binding, formation of intracellular aggregates, and decreased protein half-life. While it is unclear how these effects might lead to FSGS there are a number of theories. Firstly, protein aggregation may have a toxic effect on the podocyte. Secondly, decreased protein half-life or increased affinity for actin binding may alter actin polymerization and thereby affect the podocytes cytoskeletal architecture.[7]FSGS2: TRPC6603965A second gene associated with FSGS is TRPC6, which encodes a member of the canonical family of TRP channels. This family of ion channels conduct cations in a largely non-selective manner. As with ACTN4, TRPC6 is expressed in podocytes. While TRP channels can be activated through a variety of methods, TRPC6 is known to be activated by phospholipase C stimulation. There are at least 6 mutations in this channel, located throughout the channel. At least one of these mutations, P112Q, leads to increased intracellular calcium influx. It is unclear how this might lead to FSGS, though it has been proposed that it may result in alteration of podocyte dynamics or podocytopenia.[7]FSGS3: CD2AP607832Another gene that may be involved in hereditary forms of FSGS is the gene known as CD2AP (CD2 associated protein) or CMS (Cas binding protein with multiple SH3 domains). The protein expressed by this gene is expressed in podocytes where it interacts with fyn and synaptopodin. There is a report that a splicing mutation in this gene was found in two patients with HIV associated FSGS and this led to altered protein translation. This has been theorized to result in altered actin binding and, thus, alteration of the cytoskeletal podocyte architecture.[7]FSGS4: APOL1612551In people of African descent, two common variants in APOL1 have been associated with FSGS. It is believed that these variants arose as a defensive mechanism against Trypanosoma brucei rhodesiense or some other sub-Saharan parasite despite conferring high susceptibility to FSGS when inherited from both parents.[8]FSGS5: INF2613237Another gene associated with FSGS is INF2, which encodes a member of the formin family of actin-regulating proteins. The observation that alterations in this podocyte-expressed formin cause FSGS emphasizes the importance of fine regulation of actin polymerization in podocyte function.[9]SRN1: NPHS2600995Mutations in the NPHS2 gene, which codes for the protein called podocin,[10] can cause focal segmental glomerulosclerosis.[11] This is a recessive form of FSGS.[12] An affected individual has two mutant copies of the NPHS2 gene, in contrast to ACTN4 and TRPC6 mediated forms of disease, which are dominant and require only one mutant copy of the gene. NPHS2-mediated FSGS is resistant to treatment with steroids.
FSGS1:
ACTN4603278The first gene involved with this disorder is ACTN4, which encodes alpha-actinin 4. This protein crosslinks bundles of actin filaments and is present in the podocyte. Mutations in this protein associated with FSGS result in increased affinity for actin binding, formation of intracellular aggregates, and decreased protein half-life. While it is unclear how these effects might lead to FSGS there are a number of theories. Firstly, protein aggregation may have a toxic effect on the podocyte. Secondly, decreased protein half-life or increased affinity for actin binding may alter actin polymerization and thereby affect the podocytes cytoskeletal architecture.[7]FSGS2: TRPC6603965A second gene associated with FSGS is TRPC6, which encodes a member of the canonical family of TRP channels. This family of ion channels conduct cations in a largely non-selective manner. As with ACTN4, TRPC6 is expressed in podocytes. While TRP channels can be activated through a variety of methods, TRPC6 is known to be activated by phospholipase C stimulation. There are at least 6 mutations in this channel, located throughout the channel. At least one of these mutations, P112Q, leads to increased intracellular calcium influx. It is unclear how this might lead to FSGS, though it has been proposed that it may result in alteration of podocyte dynamics or podocytopenia.[7]FSGS3: CD2AP607832Another gene that may be involved in hereditary forms of FSGS is the gene known as CD2AP (CD2 associated protein) or CMS (Cas binding protein with multiple SH3 domains). The protein expressed by this gene is expressed in podocytes where it interacts with fyn and synaptopodin. There is a report that a splicing mutation in this gene was found in two patients with HIV associated FSGS and this led to altered protein translation. This has been theorized to result in altered actin binding and, thus, alteration of the cytoskeletal podocyte architecture.[7]FSGS4: APOL1612551In people of African descent, two common variants in APOL1 have been associated with FSGS. It is believed that these variants arose as a defensive mechanism against Trypanosoma brucei rhodesiense or some other sub-Saharan parasite despite conferring high susceptibility to FSGS when inherited from both parents.[8]FSGS5: INF2613237Another gene associated with FSGS is INF2, which encodes a member of the formin family of actin-regulating proteins. The observation that alterations in this podocyte-expressed formin cause FSGS emphasizes the importance of fine regulation of actin polymerization in podocyte function.[9]SRN1: NPHS2600995Mutations in the NPHS2 gene, which codes for the protein called podocin,[10] can cause focal segmental glomerulosclerosis.[11] This is a recessive form of FSGS.[12] An affected individual has two mutant copies of the NPHS2 gene, in contrast to ACTN4 and TRPC6 mediated forms of disease, which are dominant and require only one mutant copy of the gene. NPHS2-mediated FSGS is resistant to treatment with steroids.
Gene
OMIMDescriptionFSGS1: ACTN4603278The first gene involved with this disorder is ACTN4, which encodes alpha-actinin 4. This protein crosslinks bundles of actin filaments and is present in the podocyte. Mutations in this protein associated with FSGS result in increased affinity for actin binding, formation of intracellular aggregates, and decreased protein half-life. While it is unclear how these effects might lead to FSGS there are a number of theories. Firstly, protein aggregation may have a toxic effect on the podocyte. Secondly, decreased protein half-life or increased affinity for actin binding may alter actin polymerization and thereby affect the podocytes cytoskeletal architecture.[7]FSGS2: TRPC6603965A second gene associated with FSGS is TRPC6, which encodes a member of the canonical family of TRP channels. This family of ion channels conduct cations in a largely non-selective manner. As with ACTN4, TRPC6 is expressed in podocytes. While TRP channels can be activated through a variety of methods, TRPC6 is known to be activated by phospholipase C stimulation. There are at least 6 mutations in this channel, located throughout the channel. At least one of these mutations, P112Q, leads to increased intracellular calcium influx. It is unclear how this might lead to FSGS, though it has been proposed that it may result in alteration of podocyte dynamics or podocytopenia.[7]FSGS3: CD2AP607832Another gene that may be involved in hereditary forms of FSGS is the gene known as CD2AP (CD2 associated protein) or CMS (Cas binding protein with multiple SH3 domains). The protein expressed by this gene is expressed in podocytes where it interacts with fyn and synaptopodin. There is a report that a splicing mutation in this gene was found in two patients with HIV associated FSGS and this led to altered protein translation. This has been theorized to result in altered actin binding and, thus, alteration of the cytoskeletal podocyte architecture.[7]FSGS4: APOL1612551In people of African descent, two common variants in APOL1 have been associated with FSGS. It is believed that these variants arose as a defensive mechanism against Trypanosoma brucei rhodesiense or some other sub-Saharan parasite despite conferring high susceptibility to FSGS when inherited from both parents.[8]FSGS5: INF2613237Another gene associated with FSGS is INF2, which encodes a member of the formin family of actin-regulating proteins. The observation that alterations in this podocyte-expressed formin cause FSGS emphasizes the importance of fine regulation of actin polymerization in podocyte function.[9]SRN1: NPHS2600995Mutations in the NPHS2 gene, which codes for the protein called podocin,[10] can cause focal segmental glomerulosclerosis.[11] This is a recessive form of FSGS.[12] An affected individual has two mutant copies of the NPHS2 gene, in contrast to ACTN4 and TRPC6 mediated forms of disease, which are dominant and require only one mutant copy of the gene. NPHS2-mediated FSGS is resistant to treatment with steroids.
FSGS1:
ACTN4603278The first gene involved with this disorder is ACTN4, which encodes alpha-actinin 4. This protein crosslinks bundles of actin filaments and is present in the podocyte. Mutations in this protein associated with FSGS result in increased affinity for actin binding, formation of intracellular aggregates, and decreased protein half-life. While it is unclear how these effects might lead to FSGS there are a number of theories. Firstly, protein aggregation may have a toxic effect on the podocyte. Secondly, decreased protein half-life or increased affinity for actin binding may alter actin polymerization and thereby affect the podocytes cytoskeletal architecture.[7]FSGS2: TRPC6603965A second gene associated with FSGS is TRPC6, which encodes a member of the canonical family of TRP channels. This family of ion channels conduct cations in a largely non-selective manner. As with ACTN4, TRPC6 is expressed in podocytes. While TRP channels can be activated through a variety of methods, TRPC6 is known to be activated by phospholipase C stimulation. There are at least 6 mutations in this channel, located throughout the channel. At least one of these mutations, P112Q, leads to increased intracellular calcium influx. It is unclear how this might lead to FSGS, though it has been proposed that it may result in alteration of podocyte dynamics or podocytopenia.[7]FSGS3: CD2AP607832Another gene that may be involved in hereditary forms of FSGS is the gene known as CD2AP (CD2 associated protein) or CMS (Cas binding protein with multiple SH3 domains). The protein expressed by this gene is expressed in podocytes where it interacts with fyn and synaptopodin. There is a report that a splicing mutation in this gene was found in two patients with HIV associated FSGS and this led to altered protein translation. This has been theorized to result in altered actin binding and, thus, alteration of the cytoskeletal podocyte architecture.[7]FSGS4: APOL1612551In people of African descent, two common variants in APOL1 have been associated with FSGS. It is believed that these variants arose as a defensive mechanism against Trypanosoma brucei rhodesiense or some other sub-Saharan parasite despite conferring high susceptibility to FSGS when inherited from both parents.[8]FSGS5: INF2613237Another gene associated with FSGS is INF2, which encodes a member of the formin family of actin-regulating proteins. The observation that alterations in this podocyte-expressed formin cause FSGS emphasizes the importance of fine regulation of actin polymerization in podocyte function.[9]SRN1: NPHS2600995Mutations in the NPHS2 gene, which codes for the protein called podocin,[10] can cause focal segmental glomerulosclerosis.[11] This is a recessive form of FSGS.[12] An affected individual has two mutant copies of the NPHS2 gene, in contrast to ACTN4 and TRPC6 mediated forms of disease, which are dominant and require only one mutant copy of the gene. NPHS2-mediated FSGS is resistant to treatment with steroids.
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