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Mutational analysis of the NPHP4 gene in 250 patients with nephronophthisis

MPG-Autoren
http://pubman.mpdl.mpg.de/cone/persons/resource/persons50580

Sudbrak,  Ralf
Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons50488

Reinhardt,  Richard
High Throughput Technologies, Max Planck Institute for Molecular Genetics, Max Planck Society;

Lehrack,  Silvia
Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons50200

Hennig,  Steffen
Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Hoefle et al. - Hum Mutat.pdf
(beliebiger Volltext), 131KB

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Zitation

Hoefele, J., Sudbrak, R., Reinhardt, R., Lehrack, S., Hennig, S., Imm, A., et al. (2005). Mutational analysis of the NPHP4 gene in 250 patients with nephronophthisis. Human Mutation, 25(4), 411-411. doi:10.1002/humu.9326.


Zitierlink: http://hdl.handle.net/11858/00-001M-0000-0010-86AA-3
Zusammenfassung
Nephronophthisis (NPH), a recessive cystic kidney disease, is the most frequent genetic cause for end-stage renal disease in the first two decades of life. Mutations in three genes (NPHP1, 2, and 3) were identified as causative. Extrarenal manifestations are known, such as retinitis pigmentosa (Senior-Løken syndrome, SLS) and ocular motor apraxia type Cogan. Recently, we identified a novel gene (NPHP4) as mutated in NPH. To date, a total of only 13 different NPHP4 mutations have been described. To determine the frequency of NPHP4 mutations, we performed mutational analysis by direct sequencing of all 30 NPHP4 exons in 250 different patients with isolated NPH, SLS, or Cogan syndrome ascertained worldwide over 14 years. We identified 23 novel NPHP4 sequence variants in 26/250 different patients (10%). Interestingly, we detected homozygous or compound heterozygous mutations of NPHP4 in only 6/250 different patients (2.4%), but only one heterozygous NPHP4 sequence variant in 20/250 different patients (8%). In the six patients with two NPHP4 mutations, 5/8 mutations (63%) were likely loss-of-function mutations, whereas in the 20 patients with only one sequence variant, only 1/20 (5%) was a likely loss-of-function (i.e., truncating) mutation. We conclude that: i) two recessive mutations in NPHP4 are a rare cause of nephronophthisis; ii) single heterozygous NPHP4 sequence variants are three times more prevalent than two recessive mutations; iii) there is no genotype/phenotype correlation; iv) there must exist further genes causing nephronophthisis, since in 224/250 (90%) patients, no sequence variants in either of the four NPH genes were detected.