Disease
Disease
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.[1][2]
There is quite a wide range of different phenotypes in Lowe syndrome patients so the individual cases may vary a lot. Amongst the hallmarks of Lowe syndrome are dense congenital cataracts, some degree of intellectual impairment and mental retardation (usually severe), severe growth retardation and generalized hypotonia, proximal renal tubular dysfunction of the renal Fanconi type, which is slowly progressing towards renal failure/end-stage renal disease (ERSD) in adulthood.[1][2]
Renal tubular dysfunction is accompanied by low-molecular-weight (LMW) proteinuria in all patients. Aminoaciduria, phosphaturia, hypercalciuria, polyuria, bicarbonate, sodium and potassium wasting, renal tubular acidosis are often present as well. All affected people have impaired vision even after cataracts are removed. Hypotonia may improve a little with age, but normal state is never achieved. Hypotonia is connected with joint hypermobility which can result in joint dislocation. Almost all patients suffer from osteopenia, some patients suffer from repeated bone fractures with poor healing and in about 50 % of patients, scoliosis is present. Other frequent physical complications of Lowe syndrome are arthritis, dental malformations, bleeding disorder (platelet malfunction) and cryptorchidism (undescended testes). In some cases cysts on the skin, in the mouth, kidneys and brain were found.[1][2]
Some kinds of seizures occur in up to 50 % of patients. Behavioral problems are usually present in Lowe syndrome patients. Those may include maladaptive behaviors, obsessive-compulsive behaviors, stubbornness, repetitive behavior (such as repetitive purposeless movements), tantrums and aggressive or self-abusive behavior.[1][2]
Some of the defects, such as congenital cataracts and hypotonia, are present at birth while others evolve later. The absence of deep tendon reflexes is often observed soon after birth as well which may point to hypotonia and together with cataracts it is the first diagnostic clue. LWM proteinuria is also detected soon after birth and it is the first symptom of tubular dysfunction that appears. LMW proteinuria is present in all patients. Usually, life span is not longer than 40 years. [1][2][3]
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.[1]
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. [1][2][3]
Treatment is only symptomatic. Patients usually require more than one medical specialist to manage various clinical problems.[1][2][3] Regular surveillance by many specialists is also needed in many fields for the whole lifetime. [1][2]
OCRL-1
Domains
The 901 amino acid long OCRL1 is composed of multiple domains which enables it to interact with various partners. OCRL1 consists of an N-terminus pleckstrin homology (PH) domain without a basic patch required for phosphoinositide recognition and binding. On the other hand, it contains a loop outside of the domain fold that is involved in OCRL1 recruitment to endocytic clathrin-coated pits. [4]
PH domain is followed by one of the major conserved domains of OCRL1 which is a central polyphosphate 5-phosphatase (PH) domain, in which two characteristic motifs are present (WXGDXN(F/Y)R and P(A/S)W(C/T)DRIL separated by 60-75 amino acids (AAs)). These play an important role in both substrate binding and catalysis.[5] This domain has a Dnase I-like fold. [6]
Next up is an ASPM-SPD-2-Hydin (ASH) domain composed of nine β-strands forming two layers and a small α-helix. The β-sheet structure is similar to the immunoglobulin G fold. ASH domain also includes a Rab-binding site which mediates the interaction of OCRL1 with Rab-GTPases. This interaction is crucial for targeting OCRL1 to the Golgi complex and endosomal membranes.[7]
At a region towards the C-terminus there is a catalytically inactive Rho-GAP-like domain. It shows homology to the Rho-GAP domain found in proteins that bind and stimulate the GTPase activity of the Rho family proteins. The two reasons why this domain has no GTPase stimulating activity are: the replacement of the catalytic Arg by His and absence of a helix.[8] The ASH-RhoGAP module mediates the interactions of OCRL1 with proteins that promote specific targeting to various cellular destinations such as early endosomes, Golgi complex, lysosomes and primary cilium.[9] Since these two function as a single folding module, a destabilization in one of them will affect the stability of the other. [8]
Function
The membrane lipids phosphatidylinositol can be phosphorylated at positions 3, 4 and 5 of the inositol ring, which generates eight possible species called phosphoinositides. OCRL1 is one of the phosphatases that removes phosphate groups from specific positions of the inositol ring - OCRL1 selectively acts as a 5-phosphatase. Phosphatidylinositols together with proteins of the Rab family typically have their distinct subcellular localization, and they are both an integral part of the recognition machinery of membrane compartments, which regulates membrane trafficking between organelles. Rab GTPases regulate membrane trafficking through interactions with various effectors, one of them being the phosphatase OCRL1.
OCRL1 shows multiple binding sites for clathrin coat components (clathrin heavy chain and AP2 clathrin adaptor) so it seems to have a role in clathrin-mediated endocytosis. The two motifs involved in clathrin binding are located in the PH and Rho-GAP-like domains.[8] The 8 AA insertion in the longer isoform A enhances the interaction with clathrin (Choudhury et al., 2009, https://doi.org/10.1074/jbc.M807442200). It is recruited to clathrin‐coated pits at the later stages of the vesicle formation process.
OCRL1 phosphatase activity prevents ectopic accumulation of PtdIns(4,5)P2 [and possibly PtdIns(3,4,5)P3] on intracellular membranes to help maintain phosphoinositide spatial segregation and homeostasis within the cell (Lowe, 2005, https://doi.org/10.1016/j.devcel.2007.08.004 ).
OCRL1 has been reported to localize to the basal body and the transition zone of the primary cilium. OCRL1 participates in ciliogenesis by contributing to protein trafficking to this organelle in an Rab8/IPIP27-dependent manner (Coon et al., 2012, https://doi.org/10.1093/hmg/ddr615)
