| Conorenal syndrome | |
|---|---|
| Other names | Mainzer-Saldino syndrome or Saldino-Mainzer disease |
| Specialty | Medical genetics  |
Conorenal syndrome is a collection of medical conditions that seem to have a common genetic cause.
| Conorenal syndrome | |
|---|---|
| Other names | Mainzer-Saldino syndrome or Saldino-Mainzer disease |
| Specialty | Medical genetics |
Conorenal syndrome is a collection of medical conditions that seem to have a common genetic cause.
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The exact gene loci has not been characterized.
While it is not fully characterized as such, yet, conorenal syndrome seems to be an uncharacterized form of ciliopathy. A ciliopathy is a disease that affects the cilia (sensing cells within the body).[ citation needed ]
The link to ciliar problems as a cause for Nephronopthisis and similar Kidney diseases is relatively new. Watnick and Germino [2] note that NPHP1 and NPHP4 encode for the proteins nephrocystin and nephrocystin-4 (nephroretinin). These have been shown to interact in a series of cell-cell and cell-matrix signaling proteins. NPHP2 has been also shown to have possible links to the function of the primary renal cilium and to control of the cell cycle (Otto). [3] Otto further found that nephrocystin, inversin (INVS) and nephroretinin colocalize in the primary cilia of cultured renal epithelia cells. [3] One interesting connection is that primary cilia in renal cells may perform a sensing function which maintains the renal tubules. The loss of cystoproteins may lead to dysregulated growth.[ citation needed ]
The link to a ciliary dysfunction in the Retinal degenerative diseases also comes from Otto. Like the described Kidney diseases, Retinitis Pigmentosa is a disease where the ciliar cells (Rods and Cones) fail to thrive. In a study of patients with a disease similar to Conorenal (renal-retinal Senior-Loken) the authors state "We show that nephrocystin-5, RPGR and calmodulin can be coimmniprecipitated from retinal extracts, and that these proteins localize to connecting cilia of photoreceptors and to primary cilia of renal epithelial cells. Our studies emphasize the central role of ciliary dysfunction in the pathogenesis of renal-retinal Senior Loken Syndrome." In other words, there is a common link between certain kidney diseases and some forms of RP and it is through the something related to a problem in the cilia cells. This may be a problem in the cells themselves, or with something that keeps them alive and healthy.[ citation needed ]
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When originally characterized by Giedion, there was a relatively high mortality rate due to untreated kidney failure (end stage kidney disease - ESKD). The remarkable improvements in kidney transplantation have reduced the mortality of Conorenal Syndrome substantially if not eliminated it entirely. Most diagnosis of the disease occurs when children present with kidney failure – usually between the ages of 10 and 14. There is no known cure for the syndrome and management of the syndrome is supportive.[ citation needed ]
The syndrome was originally characterized during 1970 by Mainzer, [4] et al., in a paper published in the American Journal of Medicine. In 1979, Giedion [5] named the syndrome "conorenal syndrome" after a study of eight children. The children had chronic kidney failure and the epiphyses of their fingers were cone-shaped and protruded into the metaphysis; some also had retinitis pigmentosa (also called RP, a progressive degeneration of the retina which affects night vision and peripheral vision) or ataxia (an inability to coordinate muscular movements). In 1995, a group led by Mendley studied two siblings and determined that renal histopathologic (features that can be identified in the laboratory) and clinical features of a primarily glomerular disorder (a kidney disorder involving the glomeruli, or clusters of blood vessels that act as filters in the kidney) were features of the syndrome. [6] A recent article by Beals and Weleber (2007) also noted that a majority of patients also have small capital femoral epiphyses (the very tops of the femur where it hits the hip socket ) and/or mild abnormalities of the promixal femoral metaphysis. [7]
The cilium is a short hair-like membrane protrusion from many types of eukaryotic cell. The cilium has the shape of a slender threadlike projection that extends from the surface of the much larger cell body. Eukaryotic flagella found on sperm cells and many protozoans have a similar structure to motile cilia that enables swimming through liquids; they are longer than cilia and have a different undulating motion.
Retinitis pigmentosa (RP) is a member of a group of genetic disorders called inherited retinal dystrophy (IRD) that cause loss of vision. Symptoms include trouble seeing at night and decreasing peripheral vision. As peripheral vision worsens, people may experience "tunnel vision". Complete blindness is uncommon. Onset of symptoms is generally gradual and often begins in childhood.
A basal body is a protein structure found at the base of a eukaryotic undulipodium. The basal body was named by Theodor Wilhelm Engelmann in 1880. It is formed from a centriole and several additional protein structures, and is, essentially, a modified centriole. The basal body serves as a nucleation site for the growth of the axoneme microtubules. Centrioles, from which basal bodies are derived, act as anchoring sites for proteins that in turn anchor microtubules, and are known as the microtubule organizing center (MTOC). These microtubules provide structure and facilitate movement of vesicles and organelles within many eukaryotic cells.
Bardet–Biedl syndrome (BBS) is a ciliopathic human genetic disorder that produces many effects and affects many body systems. It is characterized by rod/cone dystrophy, polydactyly, central obesity, hypogonadism, and kidney dysfunction in some cases. Historically, slower mental processing has also been considered a principal symptom but is now not regarded as such.
Intraflagellar transport (IFT) is a bidirectional motility along axoneme microtubules that is essential for the formation (ciliogenesis) and maintenance of most eukaryotic cilia and flagella. It is thought to be required to build all cilia that assemble within a membrane projection from the cell surface. Plasmodium falciparum cilia and the sperm flagella of Drosophila are examples of cilia that assemble in the cytoplasm and do not require IFT. The process of IFT involves movement of large protein complexes called IFT particles or trains from the cell body to the ciliary tip and followed by their return to the cell body. The outward or anterograde movement is powered by kinesin-2 while the inward or retrograde movement is powered by cytoplasmic dynein 2/1b. The IFT particles are composed of about 20 proteins organized in two subcomplexes called complex A and B.
Nephronophthisis is a genetic disorder of the kidneys which affects children. It is classified as a medullary cystic kidney disease. The disorder is inherited in an autosomal recessive fashion and, although rare, is the most common genetic cause of childhood kidney failure. It is a form of ciliopathy. Its incidence has been estimated to be 0.9 cases per million people in the United States, and 1 in 50,000 births in Canada.
Senior–Løken syndrome is a congenital eye disorder, first characterized in 1961. It is a rare, ciliopathic, autosomal recessive disorder characterized by juvenile nephronophthis and progressive eye disease.
X-linked retinitis pigmentosa GTPase regulator is a GTPase-binding protein that in humans is encoded by the RPGR gene. The gene is located on the X-chromosome and is commonly associated with X-linked retinitis pigmentosa (XLRP). In photoreceptor cells, RPGR is localized in the connecting cilium which connects the protein-synthesizing inner segment to the photosensitive outer segment and is involved in the modulation of cargo trafficked between the two segments.
Nephrocystin-1 is a protein that in humans is encoded by the NPHP1 gene.
Centrosomal protein of 290 kDa is a protein that in humans is encoded by the CEP290 gene. CEP290 is located on the Q arm of chromosome 12.
Inversin is a protein that in humans is encoded by the INVS gene.
Nephrocystin-4 is a protein that in humans is encoded by the NPHP4 gene.
IQ calmodulin-binding motif-containing protein 1 is a protein that in humans is encoded by the IQCB1 gene.
A ciliopathy is any genetic disorder that affects the cellular cilia or the cilia anchoring structures, the basal bodies, or ciliary function. Primary cilia are important in guiding the process of development, so abnormal ciliary function while an embryo is developing can lead to a set of malformations that can occur regardless of the particular genetic problem. The similarity of the clinical features of these developmental disorders means that they form a recognizable cluster of syndromes, loosely attributed to abnormal ciliary function and hence called ciliopathies. Regardless of the actual genetic cause, it is clustering of a set of characteristic physiological features which define whether a syndrome is a ciliopathy.
Orofaciodigital syndrome 1 (OFD1), also called Papillon-Léage and Psaume syndrome, is an X-linked congenital disorder characterized by malformations of the face, oral cavity, and digits with polycystic kidney disease and variable involvement of the central nervous system.
RPGRIP1L is a human gene.
A BBSome is a protein complex that operates in primary cilia biogenesis, homeostasis, and intraflagellar transport (IFT). The BBSome recognizes cargo proteins and signaling molecules like G-protein coupled receptors (GPCRs) on the ciliary membrane and helps transport them to and from the primary cilia. Primary cilia are nonmotile microtubule projections that function like antennae and are found in many types of cells. They receive various environmental signals to aid the cell in survival. They can detect photons by concentrating rhodopsin, a light receptor that converts photons into chemical signals, or odorants by concentrating olfactory receptors on the primary cilia surface. Primary cilia are also meaningful in cell development and signaling. They do not contain any way to make proteins within the primary cilia, so the BBSome aids in transporting essential proteins to, from, and within the cilia. Examples of cargo proteins that the BBSome is responsible for ferrying include smoothened, polycystic-1 (PC1), and several G-Protein coupled receptors (GPCRs) like somatostatin receptors (Sstr3), melanin-concentrating hormone receptor 1 (Mchr1), and neuropeptide Y2 receptor.
Ciliogenesis is defined as the building of the cell's antenna or extracellular fluid mediation mechanism. It includes the assembly and disassembly of the cilia during the cell cycle. Cilia are important appendages of cells and are involved in numerous activities such as cell signaling, processing developmental signals, and directing the flow of fluids such as mucus over and around cells. Due to the importance of these cell processes, defects in ciliogenesis can lead to numerous human diseases related to non-functioning cilia known as ciliopathies.
IFT140, Intraflagellar transport 140 homolog, is a protein that in humans is encoded by the IFT140 gene. The gene product forms a core component of IFT-A complex which is indipensible for retrograde intraflagellar transport within the primary cilium.
Pleasantine Mill is a cell biologist and group leader at the MRC Human Genetics Unit at the University of Edinburgh. She won the 2018 British Society for Cell Biology Women in Cell Biology Early Career Medal.