Sandbox 208: Difference between revisions

Line 48:

Finally, the Rab protein enters its functional cycle whereas GDI is released into the cytosol.

= ~~Disease~~ =

= RabGDI deficiency and diseases =

Gdi1 encoding α-GDI, which is specific for Rab3. Gdi1, one of the genes involved in the control of cycling between active and inactive state of Rab familly has a major role in mental disorder. Because the Rab3 proteins may play an important role in neurotransmitter release and are substrates for GDI, Gdi1 was a potential candidate for Nonspecific X-linked mental retardation (MRX). Mutation in Gdi1 were found in patients from two families, MRX48 and MRX41.

The mutation in family MRX48 was a C -> T transition at position 366 of the cDNA. The mutation introduced a premature stop codon (TGA; R70X), and the truncated message could possible lead to synthesis of a putative peptide of 69 amino acids in length (which is likely to be unstable and degraded). It disrupts synthesis of α-GDI by introducing a premature stop codon in the open reading frame. The mutation has a dominant phenotypic effect as a carrier females in the family are also effected.

The second mutation, in the MRX41 family, xas a T -> C transition at position 433 of the cDNA, causing a missense mutation and a non-conservative amino acid change (L92P). Mutation of residues forming the patform can lead to a greater than 60-fold decrease in Rab binding and concomitant loss of function in Rab3A recycling. This residue is involved in binding of the C-terminus of Rab via interaction with Val191 and Leu193 and induces a 90° turn in the C-terminus, which directs it over the effector loop toward the lipid-binding site. Mutation is this hydrophobic patch are expected have a two fold effect.The L92P mutation affects a conserved residue in the α-helix beneath the Rab-binding platform and adjacent to a hydrophobic pocket potentially involved in binding of the geranylgeranyl group attached to the C-terminus of Rab proteins. This mutation leads to a 6,3-fold decrease in affinity for Rab3A. The mutant α-GDI may not be able to efficiently recycle Rab proteins in vivo. The introduction of the helix-breaking proline residue at position 92 may either indirectly destabilize the adjacent Rab binding region or reduce the ability of α-GDI to recognize the C-terminus prenyl group required for high affinity binding during recycling. As carrier females in the family are not affected, it is likely that the residual α-GDI activity in cells where the mutated X chromosome is active is sufficient for some vesicle cycling.

In addition to their role in neurotransmitter release at the synapse, Rab proteins regulate vesicular traffic throughout the exocytic and endocytic pathways. This ubiquitous function suggested that in neuronal tissues α-GDI also may be necessary, and that impairment of such putative function may be the cause of mental retardation. The major effect of both mutations could eventually be to greatty decrease the pool of Rab proteins available for synaptic vesicles cycling and neurotransmitter release.

Membrane trafficking leading to neural development and function of the synapse is dependent on a specific role for α-GDI. Gdi1 in one of the few genes shown to be involved in determining human intellectual abilities and the first that is associated with a fragile site.

GDI1, one of the genes involved in the control of cycling between active and inactive state of the Rab family, has a major role in mental disorder. In fact, Gdi1 encodes α-GDI, which is specific for Rab3. Rab3 plays an important role in neurotransmitter release. Therefore, mutations in GDI1 cause functional and developmental alterations in the neuron which could lead to a severe impairment of learning abilities. More precisely, mutations in GDI1 are linked to X-linked nonspecific mental retardation. Two kinds of alterations in the GDI1 gene could be found and they determine two families affected with X-linked non-specific mental retardation (MRX48 and MRX41).

In the family MRX48, there is a C -> T transition at position 366. The mutation disrupts synthesis of alpha-GDI by introducing a premature stop codon in the open reading frame. The mutation has a dominant phenotypic effect as carrier females in the family are also affected.

The second mutation, in the MRX41 family, is a T -> C transition at position 433, causing a missense mutation and a non-conservative amino acid change (L92P). This mutation leads to a 6,3-fold decrease in affinity for Rab3A. The mutant α-GDI may not be able to efficiently recycle Rab proteins in vivo. The introduction of the helix-breaking proline residue at position 92 may either indirectly destabilize the adjacent Rab binding region or reduce the ability of alpha-GDI to recognize the C-terminus prenyl group required for high affinity binding during recycling.

The major effect of both mutations could lead to a decrease of the Rab pool available for synaptic vesicles cycling and neurotransmitter release.

= Additional ressources =

= References =

Sandbox 208: Difference between revisions

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@@ Line 48: / Line 48: @@
 Finally, the Rab protein enters its functional cycle whereas GDI is released into the cytosol.
-= Disease =
+= RabGDI deficiency and diseases =
-Gdi1 encoding α-GDI, which is specific for Rab3. Gdi1, one of the genes involved in the control of cycling between active and inactive state of Rab familly has a major role in mental disorder. Because the Rab3 proteins may play an important role in neurotransmitter release and are substrates for GDI, Gdi1 was a potential candidate for Nonspecific X-linked mental retardation (MRX). Mutation in Gdi1 were found in patients from two families, MRX48 and MRX41.
-The mutation in family MRX48 was a C -> T transition at position 366 of the cDNA. The mutation introduced a premature stop codon (TGA; R70X), and the truncated message could possible lead to synthesis of a putative peptide of 69 amino acids in length (which is likely to be unstable and degraded). It disrupts synthesis of α-GDI by introducing a premature stop codon in the open reading frame. The mutation has a dominant phenotypic effect as a carrier females in the family are also effected.
-The second mutation, in the MRX41 family, xas a T -> C transition at position 433 of the cDNA, causing a missense mutation and a non-conservative amino acid change (L92P). Mutation of residues forming the patform can lead to a greater than 60-fold decrease in Rab binding and concomitant loss of function in Rab3A recycling. This residue is involved in binding of the C-terminus of Rab via interaction with Val191 and Leu193 and  induces a 90° turn in the C-terminus, which directs it over the effector loop toward the lipid-binding site. Mutation is this hydrophobic patch are expected have a two fold effect.The L92P mutation affects a conserved residue in the α-helix beneath the Rab-binding platform and adjacent to a hydrophobic pocket potentially involved in binding of the geranylgeranyl group attached to the C-terminus of Rab proteins. This mutation leads to a 6,3-fold decrease in affinity for Rab3A. The mutant α-GDI may not be able to efficiently recycle Rab proteins in vivo. The introduction of the helix-breaking proline residue at position 92 may either indirectly destabilize the adjacent Rab binding region or reduce the ability of α-GDI to recognize the C-terminus prenyl group required for high affinity binding during recycling. As carrier females in the family are not affected, it is likely that the residual α-GDI activity in cells where the mutated X chromosome is active is sufficient for some vesicle cycling.
-In addition to their role in neurotransmitter release at the synapse, Rab proteins regulate vesicular traffic throughout the exocytic and endocytic pathways. This ubiquitous function suggested that in neuronal tissues α-GDI also may be necessary, and that impairment of such putative function may be the cause of mental retardation. The major effect of both mutations could eventually be to greatty decrease the pool of Rab proteins available for synaptic vesicles cycling and neurotransmitter release.
-Membrane trafficking leading to neural development and function of the synapse is dependent on a specific role for α-GDI. Gdi1 in one of the few genes shown to be involved in determining human intellectual abilities and the first that is associated with a fragile site.
+GDI1, one of the genes involved in the control of cycling between active and inactive state of the Rab family, has a major role in mental disorder.  In fact, Gdi1 encodes α-GDI, which is specific for Rab3. Rab3 plays an important role in neurotransmitter release. Therefore, mutations in GDI1 cause functional and developmental alterations in the neuron which could lead to a severe impairment of learning abilities. More precisely, mutations in GDI1 are linked to X-linked nonspecific mental retardation. Two kinds of alterations in the GDI1 gene could be found and they determine two families affected with X-linked non-specific mental retardation (MRX48 and MRX41).
+In the family MRX48, there is a C -> T transition at position 366. The mutation disrupts synthesis of alpha-GDI by introducing a premature stop codon in the open reading frame. The mutation has a dominant phenotypic effect as carrier females in the family are also affected.
+The second mutation, in the MRX41 family, is a T -> C transition at position 433, causing a missense mutation and a non-conservative amino acid change (L92P). This mutation leads to a 6,3-fold decrease in affinity for Rab3A. The mutant α-GDI may not be able to efficiently recycle Rab proteins in vivo. The introduction of the helix-breaking proline residue at position 92 may either indirectly destabilize the adjacent Rab binding region or reduce the ability of alpha-GDI to recognize the C-terminus prenyl group required for high affinity binding during recycling.
+The major effect of both mutations could lead to a decrease of the Rab pool available for synaptic vesicles cycling and neurotransmitter release.
 = Additional ressources =
 = References =