Lack of large, homozygous deletions of the nephronophthisis 1 region in Joubert syndrome type B
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Genetic renal disease Original article
Lack of large, homozygous deletions of the nephronophthisis 1 region in Joubert syndrome type B Friedhelm Hildebrandt1, Hans Gerd Nothwang1, Urs VossmerbaÈumer1, Cornelia Springer1, Brigitte Strahm1, Bernd Hoppe2, Burkhard Keuth2, Arno Fuchshuber1, Uwe Querfeld2, Thomas J Neuhaus3, Matthias Brandis1, and members of the APN Study Group* University Children's Hospital, Freiburg University, Freiburg, Germany University Children's Hospital, Cologne University, Cologne, Germany 3 University Children's Hospital, Zurich University, Zurich, Switzerland 1 2
Received February 18, 1997; received in revised form and accepted June 26, 1997
Abstract. Joubert syndrome type B (JSB) is a developmental disorder of the nephronophthisis (NPH) complex with multiple organ involvement, including NPH, coloboma of the eye, aplasia of the cerebellar vermis, and the facultative symptoms of psychomotor retardation, polydactyly, and neonatal tachypnea. In isolated autosomal recessive NPH type 1 (NPH1), homozygous deletions have been described as causative in more than 80% of patients. Since different combinations of the extrarenal symptoms with NPH occur in JSB, a contiguous gene deletion syndrome in the NPH1 genetic region would seem a highly likely cause for JSB. We therefore examined 11 families with JSB for the presence of extended deletions at the NPH1 locus. Genomic DNA was examined using four consecutive polymerase chain reaction (PCR) markers that are deleted in NPH1 and three PCR makers flanking the NPH1 deletion. In all seven markers examined, there was no homozygous deletion detected in any of the 11 JSB families studied. Since these markers saturate the NPH1 deletion region at high density, this finding excludes the presence of large homozygous deletions of the NPH1 region in these JSB families, making it unlikely that deletions of the NPH1 region are a primary cause for JSB. Key words: Joubert syndrome ± Nephronophthisis ± Coloboma of the eye ± Cerebellar vermis aplasia
Introduction Joubert syndrome type B (JSB) is a developmental disorder of the nephronophthisis (NPH) complex [1] with multiple
organ involvement, including the renal cystic disorder NPH, retinal dystrophy or coloboma of the eye with nystagmus or oculomotor apraxia, partial or complete aplasia of the cerebellar vermis with cerebellar ataxia, and the facultative symptoms of psychomotor retardation, polydactyly and episodic tachypnea/apnea in the neonatal period [2, 3]. Familial juvenile NPH [4, 5] is an autosomal recessive renal disease of unknown etiology, characterized by the development of cysts at the cortico-medullary junction of the kidneys [6]. End-stage renal failure develops at around 13 years of age, following the initial symptoms of polyuria, polydipsia, anemia, and growth retardation. NPH is the commonest genetic cause for end-stage renal disease (ESRD) in childhood, accounting for up to 15% of ESRD in children in Europe [7]. In isolated autosomal recessive NPH type 1 (NPH1), homozygous deletions of the NPH1 regio
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