Nephronophthisis and Medullary Cystic Kidney Disease

Abstract

Nephronophthisis (NPHP) is an autosomal recessive kidney disease that inevitably progresses to end-stage kidney failure within the first three decades of life. NPHP can present as isolated kidney disease or as a syndromic ciliopathy accompanied by numerous extrarenal manifestations. Advances in next-generation sequencing have rapidly accelerated the discovery of mutaged genes that cause NPHP and have identified the cilia—basal body—centrosome complex as central for its pathogenesis. Numerous cellular pathways such as Wnt, Sonic Hedgehog, DNA damage response signaling, cell cycle control, and mitotic spindle orientation have been implicated into the pathogenesis of NPHP.

Keywords

nephronophthisis, medullary-cystic kidney disease, monogenic kidney diseases, renal ciliopathies, tubulointerstitial fibrosis, renal cysts, mutational analysis, next-generation sequencing, inherited forms of end-stage renal disease

Nephronophthisis (NPHP) and medullary cystic kidney disease (MCKD) represent a set of rare genetic kidney diseases with a similar kidney histopathology, which includes interstitial fibrosis with tubular atrophy, changes in the tubular basement membrane (TBM), and cyst formation. These two diseases can be distinguished clinically by their inheritance pattern and often by their age of onset. NPHP has an autosomal recessive inheritance pattern and results in end-stage kidney disease (ESKD) within the first three decades of life. MCKD has an autosomal dominant inheritance pattern and usually results in ESKD between the fourth and seventh decades of life. While NPHP is frequently accompanied by defects in various other organ systems, gout is the only extrarenal manifestation described in MCKD thus far ( Table 41.1 ).

Table 41.1

Genetic Causes of Nephronophthisis and Medullary Cystic Kidney Disease

Disease	Gene	Protein	Mode of Inheritance	Chromosomal Localization	Extrarenal Manifestations
NPHP1	NPHP1	Nephrocystin 1	AR	2q13	Retinitis pigmentosa, oculomotor apraxia, cerebellar vermis hypoplasia (rare)
NPHP2	INVS	Inversin	AR	9q31.1	Retinitis pigmentosa, situs inversus , liver fibrosis, pulmonary hypoplasia
NPHP3	NPHP3	Nephrocystin 3	AR	3q22.1	Retinitis pigmentosa, liver fibrosis, Meckel-Gruber syndrome
NPHP4	NPHP4	Nephroretinin	AR	1q36.22	Retinitis pigmentosa, oculomotor apraxia
NPHP5	IQCB1	Nephrocystin 5	AR	3q13.33	Retinitis pigmentosa (all described cases)
NPHP6	CEP290	Nephrocystin 6	AR	12q21.32	Retinitis pigmentosa, cerebellar vermis hypoplasia, liver fibrosis, Meckel-Gruber syndrome
NPHP7	GLIS2	GLIS 2	AR	16p13.3	Not reported
NPHP8	RPGRIP1L	Nephrocystin 8	AR	16q12.2	Retinitis pigmentosa, cerebellar vermis hypoplasia, liver fibrosis, Meckel-Gruber syndrome
NPHP9	NEK8	NEK8	AR	17q11.2	Liver fibrosis, congenital heart defects, Meckel-Gruber syndrome
NPHP10	SDCCAG8	SDCCAG8	AR	1q43–q44	Retinitis pigmentosa, Bardet-Biedl syndrome
NPHP11	TMEM67	Meckelin	AR	8q22.1	Retinitis pigmentosa, cerebellar vermis hypoplasia, liver fibrosis, polydactyly, Meckel-Gruber syndrome
NPHP12	TTC21B	TTC21B	AR	2q24.3	Cerebellar vermis hypoplasia, skeletal involvement
NPHP13	WDR19	WDR19/IFT144	AR	4p14	Retinitis pigmentosa, skeletal involvement, liver fibrosis
NPHP14	ZNF423	ZNF423	AR	16q12.1	Retinitis pigmentosa, cerebellar vermis hypoplasia
NPHP15	CEP164	CEP164	AR	11q23.3	Retinitis pigmentosa, cerebellar vermis hypoplasia
NPHP16	ANKS6	ANKS6	AR	9q22.33	Liver fibrosis, congenital heart disease
NPHP17	IFT172	IFT172	AR	2p23.3	Retinitis pigmentosa, skeletal involvement, liver fibrosis
NPHP18	CEP83	CEP83/CCDC41	AR	12q22	Retinitis pigmentosa, brain involvement
NPHP19	DCDC2	DCDC2	AR	6p22.3	Liver fibrosis
NPHP20	MAPKBP1	MAPKBP1	AR	15q15.1	None reported
MCKD1	MUC1	Mucin 1	AD	1q22	Hyperuricemia, gout
MCKD2	UMOD	Uromodulin	AD	16p12.3	Hyperuricemia, gout