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Ciliopathies Downloaded from http://cshperspectives.cshlp.org/ on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press Ciliopathies Daniela A. Braun and Friedhelm Hildebrandt Division of Nephrology, Harvard Medical School, Boston Children’s Hospital, Boston, Massachusetts 02115 Correspondence: [email protected] Nephronophthisis-related ciliopathies (NPHP-RC) are a group of inherited diseases that affect genes encoding proteins that localize to primary cilia or centrosomes. With few exceptions, ciliopathies are inherited in an autosomal recessive manner, and affected indi- viduals manifest early during childhood or adolescence. NPHP-RC are genetically very heterogeneous, and, currently, mutations in more than 90 genes have been described as single-gene causes. The phenotypes of NPHP-RC are very diverse, and include cystic-fibrotic kidney disease, brain developmental defects, retinal degeneration, skeletal deformities, facial dimorphism, and, in some cases, laterality defects, and congenital heart disease. Mutations in the same gene can give rise to diverse phenotypes depending on the mutated allele. At the same time, there is broad phenotypic overlap between different monogenic genes. The identification of monogenic causes of ciliopathies has furthered the understand- ing of molecular mechanism and cellular pathways involved in the pathogenesis. ilia are organelles that are present on the dyskinesia and Kartagener syndrome (OMIM Capical surface of almost every cell type in #244400), which is characterized by impaired various tissues and organs. They are involved mucociliary clearance resulting in recurrent in- in a variety of cellular functions such as planar fections of the upper respiratory tract, recurrent cell polarity, cell-cycle regulation and mechano- pneumonia, and progressive destruction of sensation. Furthermore, cilia integrate multiple functional respiratory tissue. Additional disease signaling pathways that are of critical impor- symptoms include heterotaxy, congenital heart tance for vertebrate development and organ dif- disease, asplenia, infertility, and situs inversus in ferentiation. Hence, ciliary dysfunction gives 50% of patients (Leigh et al. 2009). Disruption rise to a wide spectrum of human disease phe- of primary cilia has first been linked to autoso- notypes involving various organ systems. Cilia mal-recessive and autosomal-dominant poly- can be categorized as motile cilia and immotile cystic kidney diseases, which are discussed in cilia, also known as primary cilia. Motile cilia more detail in Ma et al. (2016). In contrast to are present on respiratory epithelial cells, epen- polycystic kidney disease that typically presents dymal cells of cerebrospinal fluid spaces, sperm with enlarged kidneys and massive cysts, the cells, and cells of the embryonic node during second group of cilia-related cystic kidney dis- development. Dysfunction of motile cilia re- eases, the group of nephronophthisis-related sults in the human phenotype of primary ciliary ciliopathies (NPHP-RC), rather presents with Editors: Wallace Marshall and Renata Basto Additional Perspectives on Cilia available at www.cshperspectives.org Copyright # 2017 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a028191 Cite this article as Cold Spring Harb Perspect Biol 2017;9:a028191 1 Downloaded from http://cshperspectives.cshlp.org/ on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press D.A. Braun and F. Hildebrandt shrunken or normal-sized fibrotic kidneys and of clinical symptoms is at an age of 1, 13, and 15 small cysts at the corticomedullary junction. years, respectively. In contrast to other renal The renal phenotype of NPHP frequently oc- diseases, patients usually do not develop arterial curs in a syndromic manner and is accompa- hypertension until the renal function is severely nied by anomalies in other organ systems, spe- impaired. The clinical diagnosis of NPHP is cifically retinal degeneration, cerebellar vermis typically based on renal ultrasound presenta- hypoplasia, hepatic fibrosis, skeletal anomalies, tion with normal or small-sized kidneys, in- ectodermal dysplasia, brain malformations, and creased renal echogenicity, and loss of cortico- neurological impairment. Frequently, a broad medullary differentiation. Renal cysts in NPHP phenotypic spectrum is caused by mutations are not a necessary diagnostic criterion, and, if in the same monogenic gene on an allelic basis present, are rare, remain small, and are typically (Table 1; Fig. 1). located in the corticomedullary junction re- gion. This is in contrast to autosomal-dominant or -recessive polycystic kidney disease in which NEPHRONOPHTHISIS AND RELATED cysts are large and arise from all regions of DISORDERS the kidney. Hallmarks of NPHP in renal histol- Nephronophthisis (NPHP) is an inherited dis- ogy are thickening and disintegration of the ease that represents one of the most frequent tubular basement membrane, atrophy of renal monogenic causes of end-stage renal failure tubular structure, and tubulointerstitial fibro- in children and young adults. NPHP is inherit- sis. The prevalence of NPHP does not show ed in an autosomal-recessive manner, and cur- regional clustering or gender predisposition rently mutations in up to 90 genes have been (Kleinknecht 1989). Patients with NPHP have identified as disease causing. Depending on the been described worldwide and in all ethnicities composition of the examined cohort, muta- (Kleinknecht 1989). The incidence of NPHP tions in these known monogenic genes account has been reported as nine patients/8.3 million for up to 63% of cases (Braun et al. 2015). The in the United States (Potter et al. 1980) or as one first genetic cause of NPHP, the gene NPHP1, in 50,000 live births in Canada (Waldherr et al. which encodes the protein nephrocystin was de- 1982; Pistor et al. 1985). A North American scribed in 1997 (Hildebrandt et al. 1997a; Sau- study assessing causes of end-stage renal failure nier et al. 1997). It later became apparent that in pediatric patients estimated that NPHP-relat- homozygous deletions in the NPHP1 gene are ed ciliopathies account for 5% of all cases the most frequent cause of NPHP and that mu- (Avner 1994; Warady et al. 1997). tations in this gene alone account for 20%–25% Because of shared features in renal histology, of all cases (Halbritter et al. 2013b). Each of the namely, cysts that primarily arise from the cor- subsequently identified monogenic genes ac- ticomedullary region and tubulointerstitial fi- counts only for a small fraction of affected in- brosis, NPHP was previously grouped with dividuals (Halbritter et al. 2013b). The initial medullary–cystic kidney disease (MCKD) un- clinical presentation of NPHP is typically der the term “NPHP–MCKD complex.” How- mild, and an increase in serum-creatinine, as ever, they are now considered distinct disease an indicator of impaired renal function, is typ- entities because of differences in mode of inher- ically not noted before an average age of 9 years itance, age of onset, extrarenal involvement, and (Gretz 1989). Clinical symptoms are polyuria molecular disease cause. MCKD is an autoso- with secondary enuresis, polydipsiawith regular mal-dominant disease that presents with adult- fluid intake at night, anemia, and growth retar- onset chronic kidney disease and renal salt dation (Kleinknecht 1989). Based on the age of wasting. In contrast to NPHP, end-stage renal onset, NPHP is further categorized into infan- failure typically occurs around the sixth decade tile (Gagnadoux et al. 1989), juvenile (Hilde- of life (Wolf et al. 2004). MCKD does not pre- brandt et al. 1992), and adolescent (Omran sent as a syndromic disease; the only described et al. 2000) NPHP, in which the median onset extrarenal associations are hyperuricemia and 2 Cite this article as Cold Spring Harb Perspect Biol 2017;9:a028191 Downloaded from Cite this article as Table 1. Phenotypic spectrum of 92 monogenic genes of NPHP-RC http://cshperspectives.cshlp.org/ Human disease phenotype Gene symbol Congenital OMIM (first Mode of Skeletal Laterality heart Other/ Subcellular disease description) Alias inheritance Kidney Eye Brain Liver anomalies defects disease syndromic localization Cold Spring Harb Perspect Biol Nephronopthisis (NPHP), Senior–Loken syndrome (SLS), Joubert syndrome (JBTS), Meckel–Gruber syndrome (MKS) NPHP1/ NPHP1 Nephrocystin AR NPHP, RP, OMA CVH, rare TZ SLS1/ (Hildebrandt juvenile JBTS4 et al. 1997a; Saunier et al. 1997) onOctober4,2021-PublishedbyColdSpringHarborLaboratoryPress NPHP2 INVS (Otto et al. Inversin AR NPHP, RP LF, BDP SI PH, OH TZ 2003b) infantile NPHP3/ NPHP3 (Olbrich NPHP3 AR NPHP RP LF, LC SI CHD MPD, MKS TZ MKS7/ et al. 2003) RHPD1 NPHP4/ NPHP4 (Mollet NPHP4, AR NPHP RP, OMA LF, BDP HTX CHD BB, CA 2017;9:a028191 SLS4 et al. 2002; nephroretinin Otto et al. 2002) SLS5 IQCB1 (Otto NPHP5, IQCB1 AR NPHP RP (all cases) TZ, BB et al. 2005) NPHP6/ CEP290 (Sayer CEP290, AR NPHP RP CVH, LF, BDP PD VSD, rare MKS, BBS BB SLS6/ et al. 2006; NPHP6, CBD JBTS5/ Valente et al. BBS14 MKS4/ 2006) BBS14 NPHP7 GLIS2 (Attanasio NPHP7, GLIS2 AR NPHP CA et al. 2007) NPHP8/ RPGRIP1L NPHP8, AR NPHP RP,OMA, CB CVH, LF, BDP PD MKS, BBS TZ JBTS7/ (Delous et al. RPGRIP1L CBD MKS5/ 2007) COACH NPHP9 NEK8 (Otto et al. NPHP9, NEK8 AR NPHP LF CHD MKS TZ 2008) SLS7/BBS16 SDCCAG8 (Otto SDCCAG8, AR NPHP RP ID BBS BB et al. 2010) NPHP10 Ciliopathies Continued 3 Downloaded from D.A. Braun and F. Hildebrandt 4 Table 1. Continued http://cshperspectives.cshlp.org/
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