Genetic renal disease Original article Familial ureteral abnormalities syndrome: genomic mapping, clinical findings LuAnn Klemme 1, 2 , Alfred J. Fish 1 , Stephen Rich 2, 3 , Beryl Greenberg 4 , Beverly Senske 4 , and Miriam Segall 2 1 Department of Pediatrics, University of Minnesota School of Medicine, Minneapolis, Minnesota, USA 2 Department of Laboratory Medicine and Pathology, University of Minnesota School of Medicine, Minneapolis, Minnesota, USA 3 The Institute of Human Genetics, University of Minnesota School of Medicine, Minneapolis, Minnesota, USA 4 Clinical Research Center, University of Minnesota School of Medicine, Minneapolis, Minnesota, USA Received April 29, 1997; received in revised form September 15, 1997; accepted September 22, 1997 Abstract. Abnormal development of the ureter during embryogenesis, when occurring in multiple family mem- bers, appears to be a genetically determined defect with autosomal dominant inheritance and high penetrance, which can lead to significant kidney damage, renal failure, and death. We have studied 48 individuals within a large kindred in which ureteral-related abnormalities (including vesicoureteral reflux, ureteropelvic junction obstruction, duplicated ureters, and medullary sponge kidney) were segregated. Family members who had not had previous diagnostic studies were evaluated for presence or absence of ureteral abnormalities and we attempted to map the locus for this familial ureteral abnormalities syndrome (FUAS). These studies identified 11 asymptomatic individuals, pre- viously assumed to be unaffected, with minor abnormal- ities. When linkage analysis between the inheritance of ureteral abnormalities and six marker loci glyoxalase I (GLO-1), major histocompatibility antigens (HLA-A, B, and DR/DQ), D6S288, and factor XIII antigen (F13A1) on the short arm of chromosome 6 was performed, the lod scores significantly rejected linkage over a 77.1-cM dis- tance. These findings are in contrast to previous data sug- gesting linkage between the presence of ureteral abnorm- alities and HLA, and indicate the possibility of genetic heterogeneity of FUAS. Key words: Linkage analysis ± Hydronephrosis ± Hydro- ureter ± Vesicoureteral reflux ± Inherited ureteral defects ± Chromosome 6p Introduction Structural malformations of the ureter occurring during fetal development can manifest either as a single defect, vesicoureteral reflux (VUR), ureteropelvic junction ob- struction (UPJO), and either bifid pelvis or duplicated ureters (BP/DU), or as a combination of more than one of the abnormalities [1, 2]. Several investigators have sug- gested a common embryological origin for upper and lower ureteral abnormalities (UPJO, VUR and duplicated sys- tems). Atwell et al. [3] and Weiss [4] have proposed a mechanism involving inductive interactions between the transitional epithelium which lines the bladder, ureter, and collecting ducts and the surrounding mesoblastic cells which develop into either myoblasts or fibroblasts. If all abnormalities manifested in a pedigree have such a com- mon embryological origin, the particular urinary tract ab- normality which presents in each affected individual may depend on the specific time in development during which the mutation was expressed. When studying individual nuclear families or small kindreds, it is especially difficult to determine whether these various defects are occurring independently of one another or represent different manifestations of the same gene. In the large pedigree reported here and in several smaller ones [1, 5, 6], combinations of one or more of these ureteral anomalies have been shown to segregate in a manner consistent with a single dominant mutation. Despite a large number of published pedigrees illustrating combi- nations of ureteral abnormalities within individual kin- dreds, their combined inheritance has not yet been re- cognized as a syndrome. We have studied a kindred with apparent autosomal dominant inheritance of a spectrum of ureteral abnormal- ities, including UPJO, VUR, BP/DU, and medullary sponge kidney (MSK). MSK is included in the spectrum of ureteral abnormalities observed in this kindred, since MSK patients feature cystic dilation of the collecting ducts, which are embryologically derived from the mesonephric (ureteral) duct. MSK was found in this pedigree as the only inherited abnormality in some individuals, but was also present with 349 Correspondence to: L. Klemme, Department of Pediatrics, John A. Burns School of Medicine, University of Hawaii, 1319 Punahou Street, 7th Floor, Honolulu, HI 96826 Pediatr Nephrol (1998) 12: 349 ± 356 Ó IPNA 1998