Inositol polyphosphate 5-phosphatase OCRL: Difference between revisions
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<StructureSection load='3qbt' size='340' side='right' caption='Caption for this structure' scene=''> | <StructureSection load='3qbt' size='340' side='right' caption='Caption for this structure' scene=''> | ||
== | == Oculocerebrorenal syndrome of Lowe == | ||
Lowe syndrome, formally called oculocerebrorenal syndrome, oculocerebrorenal syndrome of Lowe or OCRL, is an X-linked multisystemic disorder mainly involving eyes, nervous system (both the central and the peripheral) and kidneys. However, defects in other systems are observed as well. The syndrome is quite rare, its prevalence is 1 in 500 000 in the general population (based on the observations of the American Lowe Syndrome Association and the Italian Association of Lowe syndrome). Almost all of the patients are male. The syndrome is believed to occur worldwide as there are documented cases in America, Europe, Australia, Japan and India.<ref name="Lowe syndrome">PMID: 20301653</ref><ref name="Oculocerebrorenal">PMID: 27011217</ref> | Lowe syndrome, formally called oculocerebrorenal syndrome, oculocerebrorenal syndrome of Lowe or OCRL, is an X-linked multisystemic disorder mainly involving eyes, nervous system (both the central and the peripheral) and kidneys. However, defects in other systems are observed as well. The syndrome is quite rare, its prevalence is 1 in 500 000 in the general population (based on the observations of the American Lowe Syndrome Association and the Italian Association of Lowe syndrome). Almost all of the patients are male. The syndrome is believed to occur worldwide as there are documented cases in America, Europe, Australia, Japan and India.<ref name="Lowe syndrome">PMID: 20301653</ref><ref name="Oculocerebrorenal">PMID: 27011217</ref> | ||
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As for heterozygous females, most of them have lens opacities in post-pubertal age. Besides that, manifestations of the Lowe syndrome are usually not observed.<ref name="Lowe syndrome"/> | As for heterozygous females, most of them have lens opacities in post-pubertal age. Besides that, manifestations of the Lowe syndrome are usually not observed.<ref name="Lowe syndrome"/> | ||
== Diagnosis and treatment == | === Diagnosis and treatment === | ||
Lowe syndrome is inherited in an X-linked manner. About two-thirds of cases are transmitted by maternal carriers. Affected males are not known to reproduce. Female carriers show heterozygous female phenotype, which might indicate the need for genetic counseling. The remaining one third (approximately) is attributed to a de novo variant. There is a high risk (4,5%) of germline mosaicism in Lowe syndrome families. If OCRL pathogenic variant has been identified in a family member, prenatal genetic testing can be performed. Unfortunately, it can not say anything about the severity of the disease. <ref name="Lowe syndrome"/><ref name="Oculocerebrorenal"/><ref name="Evidence"/> | Lowe syndrome is inherited in an X-linked manner. About two-thirds of cases are transmitted by maternal carriers. Affected males are not known to reproduce. Female carriers show heterozygous female phenotype, which might indicate the need for genetic counseling. The remaining one third (approximately) is attributed to a de novo variant. There is a high risk (4,5%) of germline mosaicism in Lowe syndrome families. If OCRL pathogenic variant has been identified in a family member, prenatal genetic testing can be performed. Unfortunately, it can not say anything about the severity of the disease. <ref name="Lowe syndrome"/><ref name="Oculocerebrorenal"/><ref name="Evidence"/> | ||
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OCRL1 has been reported to localize to the basal body and the transition zone of the primary cilium. Theredore, it also participates in ciliogenesis by contributing to protein trafficking to this organelle in an Rab8/IPIP27-dependent manner.<ref name="cilia">PMID: 22228094</ref> | OCRL1 has been reported to localize to the basal body and the transition zone of the primary cilium. Theredore, it also participates in ciliogenesis by contributing to protein trafficking to this organelle in an Rab8/IPIP27-dependent manner.<ref name="cilia">PMID: 22228094</ref> | ||
== Mutations in OCRL-1 == | |||
Given the important function of OCRL-1 and the amount of its interaction partners it is not surprising that point mutations can cause the serious OCRL. Although, some mutations cause only a mild type of OCRL which is called Dent-2 disease.<ref name="com">PMID: 31967472</ref> This diseases is caused by different mutations in all domains of OCRL-1 just like OCRL.<ref name="china">PMID: 31674016</ref><raf name="com"/><ref name="FH">PMID: 21666675</ref> However, it is characterized solely by heterogeneous kidney malfunctions.<ref name="dent">PMID: 32860533</ref> Even though, certain continuum between the two diseases has been suggested, it is unclear what causes the different symptoms of various mutations.<ref name="continum">PMID: 21031565</ref> As to the OCRL-1 mutations causing OCRL so far only two have been studied closely. It is the substitution of F by V at the position 668 (F668V) and the substitution of N by K at the position 591 (N591K).<ref name="main"/><ref name="com"/> | |||
A full crystal structure of the OCRL-1 is not known but there are in total 5 structures of different domains which add up together almost the entire protein (2KIE, 2Q2V, 3QBT, 3QIS, 4CMI). What’s more, one crystal structure of partial 5‐phosphatase domain and ASH domain (AA 540-678) in interaction with Rab8a was solved (3QBT) and shows very well the interaction surface of the proteins. There are two main interaction sides. First is located in the hinge region (AA 555-559) between ASH domain and 5PD, which is represented by the single 5PD alpha helix in crystal structure of 3QBT. The most important AAs in the binding side are shown in figure. The second important binding side is located in beta-strand 9 of the ASH domain (AA 664-670).<ref name="main"/> | |||
It is clear from the structure that F668 is important in the binding side because it sits in the hydrophobic pocket of Rab8a created by I41, G42 and F70. Its substitution by V is therefore a major one since V is smaller and less hydrophobic than F. The mutation then causes disruption of this interaction and reduces the binding ability of OCRL-1 with Rab8a by almost 6 folds. Moreover, the mutation causes the protein to be mainly localized in cytoplasm which can significantly hinder its normal function which is connected with vesicular formation.<ref name="main"/> | |||
The N591K mutation also causes significant reduction in binding of Rab8a proteins but the reason for this is different than in the case of F668V mutation. This AA is not part of any binding side but it seems to be important in the maintenance of the correct features of the ASH domain which is essential for Rab8a binding. The effect of this mutation was studied in silico and it showed that the mutation causes the ASH domain to alter its flexibility and overall fold. Although the highest change was observed in the AA that surrounds the F668V mutation, the substitution caused subsequent changes in most parts of the protein which had brought about decreases of prevalence of hydrogen bonds between Rab8a and OCRL-1.<ref name="com"/> | |||
</StructureSection> | </StructureSection> | ||
== References == | == References == | ||
<references/> | <references/> | ||