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1.
Autosomal dominant medullary cystic kidney disease: evidence of gene locus heterogeneity 总被引:3,自引:2,他引:1
Fuchshuber A; Deltas C; Berthold S; Stavrou C; Vollmer M; Burton C; Feest T; Krieter D; Gal A; Brandis M; Pierides A; Hildebrandt F 《Nephrology, dialysis, transplantation》1998,13(8):1955-1957
Autosomal dominant medullary cystic kidney disease (ADMCKD; synonym:
medullary cystic disease, MCD) is an autosomal dominant kidney disorder,
sharing morphological and clinical features with recessive juvenile
nephronophthisis (NPH), such as reduced urinary concentration ability and
multiple renal cysts at the corticomedullary junction. While in NPH
end-stage renal disease (ESRD) occurs in adolescence, ADMCKD leads to ESRD
in adulthood. Recently a gene locus for ADMCKD has been localized to
chromosome 1q21 in two large Cypriot families. This prompted us to examine
linkage in three ADMCKD-families, using the same set of polymorphic
microsatellite markers spanning the critical region on chromosome 1q21.
Haplotype analysis revealed that none of the three families showed linkage
to this locus, thus demonstrating evidence for genetic locus heterogeneity.
Additional linkage analysis studies need to be performed in order to
identify further gene loci cosegregating with this autosomal dominant
kidney disorder. 相似文献
2.
A locus for adolescent and adult onset familial focal segmental glomerulosclerosis on chromosome 1q25-31 总被引:10,自引:0,他引:10
Tsukaguchi H Yager H Dawborn J Jost L Cohlmia J Abreu PF Pereira AB Pollak MR 《Journal of the American Society of Nephrology : JASN》2000,11(9):1674-1680
Focal segmental glomerulosclerosis is a nonspecific renal lesion observed both as a primary (idiopathic) entity and in a secondary form, typically in association with reduced functional renal mass. Familial forms have been observed and two loci for autosomal dominant FSGS have been mapped. This study shows that an adolescent/adult form of recessive FSGS maps to a locus on chromosome 1q25-31, which overlaps with a region previously identified as harboring a locus for an early childhood onset recessive form of nephrotic syndrome (SRN1). Evaluation of a large family demonstrated linkage with a maximum two-point lod score of 3.98 at D1S254 and D1S222. Lod score calculations support the conclusion of linkage in four of five additional families. Haplotype analysis suggests that this FSGS gene is located in a 19-cM region flanked by D1S416 and D1S413, of which 6 cM overlaps with SRN1, suggesting that these distinct clinical subsets of kidney disease may be allelic. These regions may also overlap with the syntenic region of the glomerulosclerosis susceptibility locus in the BUF/Mna rat. Because the presentation of FSGS may be subtle, inherited FSGS may be much more common than generally realized and grossly underestimated because of the absence of clear familial patterns. This result increases the suspicion that polymorphisms at this locus may contribute to sporadic FSGS. 相似文献
3.
Establishing an algorithm for molecular genetic diagnostics in 127 families with juvenile nephronophthisis 总被引:5,自引:0,他引:5
Hildebrandt F Rensing C Betz R Sommer U Birnbaum S Imm A Omran H Leipoldt M Otto E;Arbeitsgemeinschaft für Paediatrische Nephrologie 《Kidney international》2001,59(2):434-445
BACKGROUND: Juvenile nephronophthisis (NPH1), an autosomal recessive cystic disease of the kidney, represents the most common genetic cause of end-stage renal disease in the first two decades of life. On the basis of identification of the gene (NPHP1) defective in NPH1 and the presence of homozygous deletions of NPHP1 in the majority of NPH1 patients, molecular genetic diagnosis for NPH1 is now possible. Molecular genetic testing offers the only method for definite diagnosis of NPH1 and avoids invasive diagnostic measures like renal biopsy. METHODS: We examined 127 families (204 patients) with the presumed diagnosis of NPH using molecular genetic diagnostic techniques. In 68 families, renal biopsy was performed and was consistent with NPH, and in 61 families, there was more than one affected child ("multiplex families"). RESULTS: In 74 families (115 patients), there was proof of the diagnosis of NPH1 by detection of a homozygous deletion of the NPHP1 gene, and in 5 families a heterozygous deletion in combination with a point mutation in NPHP1 was demonstrated. Furthermore, for 16 families, NPH1 was excluded with high likelihood by linkage analysis, and for 20 families by detection of heterozygosity for two newly identified polymorphic markers within the deletion region. In 5 of the remaining 12 families, which were noninformative for these markers, fluorescence in situ hybridization did not detect any further heterozygous deletions. CONCLUSIONS: The diagnosis of NPH1 was proven by molecular genetic techniques in 62% of families with one or more children with the presumed diagnosis of NPH. We present evidence that there is a fourth locus for NPH, since only 6 of the 26 multiplex families in whom the diagnosis of NPH1 was excluded were compatible with linkage to other loci for NPH. On the basis of the presented data, we propose an algorithm for molecular genetic diagnostics in NPH. 相似文献
4.
K Dahan A Fuchshuber S Adamis M Smaers S Kroiss G Loute J P Cosyns F Hildebrandt C Verellen-Dumoulin Y Pirson 《Journal of the American Society of Nephrology : JASN》2001,12(11):2348-2357
Familial juvenile hyperuricemic nephropathy (FJHN) is an autosomal dominant disorder heralded by hyperuricemia during childhood; it is characterized by chronic interstitial nephritis, with marked thickening of tubular basement membranes, and leads to progressive renal failure during adulthood. A gene for FJHN in two Czech families was recently mapped to chromosome 16p11.2, close to the MCKD2 locus, which is responsible for a variant of autosomal dominant medullary cystic kidney disease observed in an Italian family. In a large Belgian family with FJHN, a tight linkage between the disorder and the marker D16S3060, located within the MCKD2 locus on chromosome 16p12 (maximal two-point logarithmic odds score of 3.74 at a recombination fraction of theta = 0), was observed in this study. The candidate region was further narrowed to a 1.3-Mb interval between D16S501 and D16S3036. Together with the striking clinical and pathologic resemblance between previously reported medullary cystic kidney disease type 2 and FJHN occurring in the Belgian family (including the presence of medullary cysts), this study suggests that these two disorders are facets of the same disease. 相似文献
5.
M Vollmer N Jeck H H Lemmink R Vargas D Feldmann M Konrad F Beekmann L P van Den Heuvel G Deschenes L M Guay-Woodford C Antignac H W Seyberth F Hildebrandt N V Knoers 《Nephrology, dialysis, transplantation》2000,15(7):970-974
BACKGROUND: Recently a locus for antenatal Bartter syndrome associated with sensorineural deafness was mapped to human chromosome 1p31 in a single consanguineous Bedouin family (Brennan et al. Am J Hum Genet 1998; 62: 355-361). METHODS: By haplotype analysis we demonstrate linkage to this locus in nine consanguineous families with antenatal Bartter syndrome associated with sensorineural deafness. RESULTS: The critical interval compatible with linkage was refined to 4.0 cM by two novel recombinational events with markers D1S2661 and D1S475. CONCLUSION: We thereby confirmed this gene locus and distinguished this clinical subtype from other variants of Bartter syndrome as a new disease entity. 相似文献
6.
Jefferson J; Lemmink H; Hughes A; Hill C; Smeets H; Doherty C; Maxwell A 《Nephrology, dialysis, transplantation》1997,12(8):1595-1599
Background: Alport syndrome is a hereditary nephritis
that may lead to end-stage renal disease (ERSD) in young adult life and is
often associated with sensorineural deafness and/or ocular abnormalities.
The majority of families are X-linked due to mutations in the COL4A5 gene
at X122. Autosomal forms of the disease are also recognized with recessive
disease, having been shown to be due to mutations in the COL4A3 and COL4A4
genes on chromosome 2. Familial benign haematuria has also been mapped to
this region in some families.Subjects and methods: We
describe a large family with autosomal dominant Alport syndrome in which
males and females are equally severely affected and one member with a mild
sensorineural deafness reached ESRD aged 35 years. Renal biopsy in four
affected patients demonstrated characteristic thickened and split
glomerular basement membranes on electron-microscopy.
Results: Genetic linkage analysis using markers on
chromosome 2q demonstrated co-segregation of the disease with the markers
D2S351 and D2S401 with a maximum lod score of 3.4 at zero recombination.
Linkage to the COL4A4 gene was confirmed using an intragenic COL4A4
polymorphism. Mutation analysis has revealed a missense Leu36Pro mutation
in exon 5 of the adjacent COL4A3 gene in the unaffected mother, which may
lead to a more severe phenotype in affected family members carrying this
mutation. Conclusion: Mutations in the COL4A3 and
COL4A4 cause a spectrum of glomerular basement membrane disease ranging
from autosomal recessive Alport syndrome to autosomal dominant Alport
syndrome and familial benign haematuria. 相似文献
7.
H Omran K H?ffner M Vollmer J Pigulla G Wagner G Caridi F Hildebrandt 《Nephrology, dialysis, transplantation》1999,14(10):2328-2331
BACKGROUND: Nephronophthisis (NPH) is an autosomal recessively transmitted kidney disease, characterized by cyst formation at the cortico-medullary junction, and a sclerosing tubulointerstitial nephropathy. Juvenile nephronophthisis (NPH1) is the most common genetic cause of renal failure in children and maps to chromosome 2q12-q13. The responsible gene NPHP1 has been identified and encodes for nephrocystin. Not all families with NPH demonstrate linkage to that locus. METHODS: We studied six families with NPH without linkage to the NPH1 locus. In order to attempt identification of a new causative gene, the candidate genes ACE (angiotensin converting enzyme) and Bcl-2 (B cell leukaemia/lymphoma 2 gene) originating from mouse models, were examined. For the six families highly polymorphic microsatellites covering the whole candidate gene regions were haplotyped and linkage analysis was performed. RESULTS: Haplotype analyses of all families examined were incompatible with linkage of the disease status to ACE or Bcl-2. Linkage analysis excluded both candidate gene regions with a LOD-score of < -2. CONCLUSIONS: This study excluded the candidate genes ACE and Bcl-2 for NPH. Additional linkage studies need to be performed in order to identify further genes responsible for nephronophthisis. 相似文献
8.
Towards the identification of (a) gene(s) for autosomal dominant medullary cystic kidney disease 总被引:1,自引:0,他引:1
Scolari F Viola BF Ghiggeri GM Caridi G Amoroso A Rampoldi L Casari G 《Journal of nephrology》2003,16(3):321-328
Medullary cystic kidney disease (MCKD) belongs with nephronophthisis (NPH) in a group of inherited tubulo-interstitial nephritis, which has been referred to as the NPH-MCKD complex. Although MCKD and NPH share morphological features, they differ in several respects. The most common variant is recessive juvenile NPH, with onset in childhood and leading to end-stage renal disease (ESRD) within the 2nd decade of life; the most frequent extrarenal involvement is tapeto-retinal degeneration. MCKD is a dominant condition recognized in later life and leading to ESRD at the age of 50 years; hyperuricemia and gout can be associated features. The first sign of MCKD is polyuria; later, the clinical findings relate to renal insufficiency. Originally, NPH and MCKD were considered separate entities. Subsequently, it has been suggested that the two diseases were a single disorder due to the clinico-pathological identity. This unifying conception was later refuted due to the identification of MCKD dominant families. Recently, considerable insight has been gained into the genetics of the NPH-MCKD complex. The majority of juvenile NPH cases are due to deletion of the NPHP1 gene on chromosome 2q13. Genes for infantile and adolescent NPH have been localized respectively to chromosome 9q22-q31 and 3q22. A new locus, NPHP4, has been recently identified on chromosome 1p36. Two genes predisposing to dominant MCKD, MCKD1 and MCKD2, have been localized to chromosome 1q21 and 16p12. Independent confirmation of the locations of MCKD1 and MCKD2 in other MCKD families, with or without hyperuricemia and gout, has been reported. The gene for familial juvenile hyperuricemic nephropathy (FJHN), a phenotype that is very similar to MCKD, was recently mapped to 16p12, in a region overlapping with the MCKD2 locus, raising the question as to whether MCKD2 and FJHN are allelic variants of the same disease entity. The ultimate proof of the allelism between MCKD2 and FJHN will be provided by the identification of the responsible gene(s). Identification and characterization of the MCKD and FJHN genes will help to clarify the pathogenesis and classification of hereditary tubulo-interstitial nephritides. 相似文献
9.
Linkage exclusion between the autosomal dominant polycystic kidney disease locus and chromosome 16 markers in a new family. 总被引:1,自引:0,他引:1
J E Brissenden J M Roscoe N E Simpson M Silverman 《Journal of the American Society of Nephrology : JASN》1991,2(4):913-919
A family segregating for autosomal dominant polycystic kidney disease (ADPKD) is reported. The clinical picture was typical for ADPKD in some family members, although others showed mild involvement. DNA from family members was probed with seven chromosome 16 single-copy DNA sequences that mapped to the telomere of the short arm of the chromosome. The most likely order of six of the probes from the telomere is palpha3'HVR.64 at the designated locus D16S85, CRI-0327 at D16S63, CRI-090 at D16S45, CRI-0129 at D16S56, CRI-0133 at D16S58, and CRI-0136 at D16S60, with the PKD1 locus for ADPKD between D16S85 and D16S63. The seventh probe 24-1 at D16S80 had not been ordered in relation to the other sequences, but PKD1 had been mapped between it and D16S85. The three probes that were informative in our family, palpha3'HVR.64, CRI-090, and CRI-0136 had been linked to the disease locus at recombination frequencies of 4% and approximately 6 and 12%, respectively. Linkage was excluded between the ADPKD locus in our family and palpha3'HVR.64 at a recombination value of up to 6%. Linkage was also excluded between CRI-090 and the disease locus at a recombination value of up to 5%. The data for linkage between CRI-0136 and the ADPKD locus in our family were inconclusive. Multipoint analysis excluded the possibility that the disease in this family lies between the flanking genetic markers that have previously been used to define the genetic interval in which the most common form of polycystic kidney disease, PKD1, lies. We have not made a positive assignment of the ADPKD mutation in this family.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
10.
Tarrass F Benjelloun M Hachim K Benghanem MG Ramdani B Zaid D Benkirane A Sqalli S 《Nephrology (Carlton, Vic.)》2006,11(2):117-119
Ehlers-Danlos syndrome (EDS), a heterogeneous disease of the connective tissues, is diagnosed by a triad of symptoms that include skin hyperextensibility, joint hypermobility and connective tissue fragility. Nephronophtisis (NPH) is an autosomal recessive interstitial nephritis leading to terminal renal insufficiency around puberty. The occurrence of these two rare diseases together is unusual. A review of the literature discloses no case of this association. We report here on a 16-year-old man with undiagnosed EDS, who was referred to our hospital because of renal insufficiency, history of polyuria and polydipsia. Renal ultrasound showed normal kidney size, with a lack of corticomedullary differentiation. Renal biopsy specimen disclosed chronic tubulointerstitial nephritis resembling NPH. Further evaluation identified hypermobile joints and hyperextensible skin, which led to the diagnosis of the EDS. These data suggest that patients with EDS need to be evaluated carefully for the presence of renal anomalies. 相似文献
11.
G Caridi L Murer R Bellantuono P Sorino DA Caringella R Gusmano GM Ghiggeri 《American journal of kidney diseases》1998,32(6):1059-1062
Tapeto-retinal degeneration is frequent in patients with nephronophthisis. Association of the most severe forms of tapeto-retinal dystrophy with NPH identifies a syndrome described first by Senior et al and Loken et al. This syndrome is distinct on molecular grounds from pure renal nephronophthisis (NPH1), which has its gene locus mapped on chromosome 2q13. We describe three families with large homozygous deletion of the NPH1 locus in which mild to moderate ocular lesions due to tapeto-retinal degeneration coexisted and were correlated to renal defects. This new association of NPH1 with retinal dystrophy is characterized by focal lesions of retina and is pauci-symptomatic in clinical presentation. For this reason it may remain unrecognized in most NPH1 patients. 相似文献
12.
New insights: nephronophthisis-medullary cystic kidney disease 总被引:8,自引:2,他引:6
Nephronophthisis (NPH) and medullary cystic kidney disease (MCKD) constitute a group of renal cystic diseases, which share
a common characteristic renal histologic triad of tubular basement membrane disintegration, tubular atrophy with cyst development,
and interstitial cell infiltration with fibrosis. The different disease variants lead to chronic renal failure with onset
at characteristic age ranges for recessive NPH and dominant MCKD. There is extensive gene locus heterogeneity with at least
three different loci for nephronophthisis (NPHP1, NPHP2, and NPHP3) and two different loci for MCKD (MCKD1 and MCKD2). Juvenile nephronophthisis, in addition, can be associated with extrarenal organ involvement. We have identified by positional
cloning the gene (NPHP1) for juvenile nephronophthisis (NPH1), as a first step towards understanding the pathogenesis of this disease group. Its
gene product, nephrocystin, is a novel protein, which contains a src-homology 3 (SH3) domain. We put forward a hypothesis that the pathogenesis of NPH might be related to signaling processes
at focal adhesions (the contact points between cells and extracellular matrix) and/or adherens junctions (the contact points
between cells).
Received: 13 July 2000 / Revised: 1 October 2000 / Accepted: 4 October 2000 相似文献
13.
The clinical spectrum of shunt nephritis 总被引:2,自引:0,他引:2
Haffner D; Schindera F; Aschoff A; Matthias S; Waldherr R; Scharer K 《Nephrology, dialysis, transplantation》1997,12(6):1143-1148
Background. Shunt nephritis is an
immune-complex-mediated glomerulonephritis (GN) associated with chronically
infected ventriculoatrial shunts inserted for treatment of hydrocephalus.
Methods. Six patients aged 5-22 years with shunt
nephritis are reported who have been observed between 1971 and 1994. The
clinical course and long-term outcome are analysed in relation to the time
of diagnosis and renal histopathology. Results. The
time of diagnosis of shunt nephritis ranged from 0.3 to 4.5 years after the
last shunt operation. Diagnosis was delayed up to 1.5 years after the first
clinical manifestations. All patients had signs of infection, i.e.
recurrent fever, hepatosplenomegaly, anaemia, and cerebral symptoms. Renal
manifestations consisted of haematuria (macroscopic in 3 patients),
proteinuria (heavy in 5), renal insufficiency (4) and hypertension (2).
Decreased C3 levels, cryoglobulins, and antinuclear factors were frequent.
Cultures of blood and cerebrospinal fluid provided growth mainly of
S. epidermidis. Renal biopsy revealed endocapillary GN
(1), membranoproliferative GN (1) and endocapillary/extracapillary GN with
crescents (2). All patients received antibiotics i.v. Complete recovery was
observed in three of four patients in whom the shunt was totally removed,
supported by transient external drainage of cerebrospinal fluid, and
followed by placement of a ventriculoperitoneal shunt. One child with
delayed diagnosis, presenting with a serum creatinine of 3.2 mg/dl,
hypertension, and severe scarring on renal biopsy, rapidly progressed to
irreversible ESRD within 5 months. Two patients without and only partial
removal of the shunt died subsequently from sepsis.
Conclusions. The renal outcome of shunt nephritis is
good if early diagnosis and treatment is provided including i.v.
antibiotics and total removal of the infected shunt. The possible
progression to ESRD requires frequent nephrological monitoring of patients
with ventriculoatrial shunts. 相似文献
14.
H Omran K H?ffner S Burth S Ala-Mello C Antignac F Hildebrandt 《Nephrology, dialysis, transplantation》2001,16(4):755-758
BACKGROUND: A new type of nephronophthisis (NPH) has been recently identified in a large Venezuelan kindred: adolescent nephronophthisis (NPH3) causes end-stage renal disease (ESRD) at a median age of 19 years. The responsible gene (NPHP3) maps to 3q21-q22. NPH3 shares with juvenile nephronophthisis (NPH1) the same disease manifestations such as polyuria, polydipsia, and secondary enuresis. Histopathological findings consist of tubular basement membrane changes, cysts at the corticomedullary junction, and a chronic sclerosing tubulointerstitial nephropathy. The only difference is a younger age at ESRD in NPH1 (median age of 13 years) when compared with NPH3. METHODS: In order to evaluate whether there might be a fourth locus of isolated nephronophthisis, we studied eight NPH families without extrarenal disease manifestations and without linkage to the NPH1 locus (NPHP1) on chromosome 2q12-q13. ESRD was reached at ages ranging from 7 to 33 years. Individuals were haplotyped with microsatellites covering the genetic locus of NPHP3. Infantile NPH (NPH2) was excluded in all families by the clinical history and histological findings. RESULTS: In four of the examined families haplotype analysis was compatible with linkage to the NPHP3 locus. In one of these families identity by descent was observed. In contrast, in another four families linkage was excluded for NPHP3. CONCLUSION: Four NPH-families were neither linked to NPHP1 nor to NPHP3, indicating further genetic heterogeneity within the group of nephronophthisis. The finding of further genetic heterogeneity in NPH has important implications for genetic counselling. 相似文献
15.
Coppo R; Gianoglio B; Porcellini M; Maringhini S 《Nephrology, dialysis, transplantation》1998,13(2):291-295
Background. Children's renal biopsy data were gathered
for 3 consecutive years (1992-1994) by the Group of Renal Immunopathology
of the Italian Society of Pediatric Nephrology, which opened a paediatric
section of the Italian Registry of Renal Biopsies. Materials.
The Registry recorded the histological diagnosis and the
clinical data at renal biopsy of 432 children ⩽15 years old (mean
age 8.96±3.7 years). Results. The most
common glomerulonephritis (GN) at renal biopsy was idiopathic IgAGN (18.8%)
and the most frequent secondary GN was Henoch-Schonlein purpura (HSP)
nephritis (11.6%). Minimal-change disease (MCD) accounted for 11.6%, focal
and segmental sclerosis (FSG) 8.5%, mesangial proliferative GN (MPGN) 9.5%,
membranoproliferative GN 5.5%, and thin-membrane disease 5%. Lupus
nephritis was diagnosed in 5% and Alport's GN in 3.9% of the cases. The
annual incidence of primary GN in Italian children was 11.1 cases per
million children population (p.m.c.p.), IgAN accounting for 3.1 cases, MCD
2.3, and HSP nephritis 1.9 cases p.m.c.p. respectively. Italian children
underwent renal biopsy because of isolated microscopic haematuria in 19.3%
of the cases, non-nephrotic proteinuria with or without microscopic
haematuria in 31.2%, and nephrotic-range proteinuria in 34.2%, less
frequently (15.3%) because of acute or chronic renal failure. Children with
persistent isolated microscopic haematuria had most frequently IgAN (34.9%)
or thin-membrane disease (25.3%), while those with non-nephrotic
proteinuria had IgAN (30.4%) and HSP nephritis (23%). In cases with
nephrotic proteinuria renal biopsy showed MCD in 34.5% of the cases, FSG in
16.9%, and MPGN in 12.2%. When renal biopsy was performed in chronic renal
failure chronic interstitial renal disease was detected in 62.5% of the
cases. Conclusions. This National Registry provides
data on the indications for performing renal biopsy in Italian children and
on the frequency and annual incidence of histological lesions detected.
IgAN, primary or related to HSP, was the most common nephritis in Italian
children undergoing renal biopsy. 相似文献
16.
S. Ala-Mello Helena Kääriäinen Olli Koskimies 《Pediatric nephrology (Berlin, Germany)》2001,16(6):507-509
Nephronophthisis (NPH) is a chronic tubulointerstitial nephritis leading to terminal renal insufficiency. The disease is heterogeneous,
but usually the inheritance pattern is autosomal recessive. In 80% of cases, the disease is caused by a homozygous deletion
in NPHP1 gene in chromosome 2q13. Ulcerative colitis is an inflammatory bowel disease with chronic diarrhea, rectal bleeding
and characteristic histological findings. Its etiology is suggested to be multifactorial, consisting of genetic susceptibility
and unknown exogenous factors. We present two siblings with NPH and ulcerative colitis. As NPH in this family is not linked
to 2q13, this association may represent a new, syndromic form of NPH.
Received: 30 August 2000 / Revised: 3 January 2001 / Accepted: 29 January 2001 相似文献
17.
Linkage of Gitelman syndrome to the thiazide-sensitive sodium-chloride cotransporter gene with identification of mutations in Dutch families 总被引:3,自引:0,他引:3
Henny H. Lemmink Lambert P. W. J. van den Heuvel Henk A. van Dijk Gerard F. M. Merkx Tineke J. Smilde Peter E. M. Taschner Leo A. H. Monnens Steve C. Hebert Nine V. A. M. Knoers 《Pediatric nephrology (Berlin, Germany)》1996,10(4):403-407
Gitelman syndrome is a mostly autosomal recessive disorder affecting the renal tubular function associated with hypokalemia
and hypomagnesemia. Functional studies point to a defect in the distal renal tubule in the thiazide-sensitive, electroneutral
sodium-chloride cotransporter (TSC). Based upon the localization of a 2.6 cDNA encoding the human TSC to chromosome 16q13,
polymorphic markers spanning the region from 16p12 to 16q21 were tested for linkage to the Gitelman syndrome locus in three
Dutch families with autosomal recessive inheritance of this disorder. Using two-point linkage analysis, a maximum LOD score
(Zmax of 4.49 (at Θ = 0.00) was found for the marker D16S408. One crucial recombination event places the Gitelman syndrome locus
distal to D16S419 at 16q12-13. Subsequently we have tested our group of Gitelman patients for mutations in the human TSC gene.
Two mutations were identified in three Gitelman families. Our study confirms that the human TSC gene is involved in Gitelman
syndrome. Patients from three Gitelman families reveal two identical human TSC mutations, suggesting these families share
a common ancestor.
Received April 19, 1996; received in revised form and accepted May 24, 1996 相似文献
18.
We have identified a region on chromosome 1q21-q24 that was significantly linked to type 2 diabetes in multiplex families of Northern European ancestry and also in Pima Indians, Amish families, and families from France and England. We sought to narrow and map this locus using a combination of linkage and association approaches by typing microsatellite markers at 1.2 and 0.5 cM densities, respectively, over a region of 37 cM (23.5 Mb). We tested linkage by parametric and nonparametric approaches and association using both case-control and family-based methods. In the 40 multiplex families that provided the previous evidence for linkage, the highest parametric, recessive logarithm of odds (LOD) score was 5.29 at marker D1S484 (168.5 cM, 157.5 Mb) without heterogeneity. Nonparametric linkage (NPL) statistics (P = 0.00009), SimWalk2 Statistic A (P = 0.0002), and sib-pair analyses (maximum likelihood score = 6.07) all mapped to the same location. The one LOD CI was narrowed to 156.8-158.9 Mb. Under recessive, two-point linkage analysis, adjacent markers D1S2675 (171.5 cM, 158.9 Mb) and D1S1679 (172 cM, 159.1 Mb) showed LOD scores >3.0. Nonparametric analyses revealed a second linkage peak at 180 cM near marker D1S1158 (163.3 Mb, NPL score 3.88, P = 0.0001), which was also supported by case-control (marker D1S194, 178 cM, 162.1 Mb; P = 0.003) and family-based (marker ATA38A05, 179 cM, 162.5 Mb; P = 0.002) association studies. We propose that the replicated linkage findings actually encompass at least two closely spaced regions, with a second susceptibility region located telomeric at 162.5-164.7 Mb. 相似文献
19.
R Torra C Badenas F Cofán L Callis L Pérez-Oller A Darnell 《Nephrology, dialysis, transplantation》1999,14(3):627-630
BACKGROUND: Genetic heterogeneity is a well-known feature of Alport syndrome (AS). Most families with AS show an X-linked dominant pattern of inheritance but about 15% of families show an autosomal inheritance of the disease. Autosomal recessive AS may account for 10% of the total number of cases and is caused by mutations in the COL4A3 and COL4A4 genes. The clinical spectrum of this rare disorder has not been well clarified. METHODS: We present two families with AS. Two affected members of these families have entered end-stage renal disease (ESRD) in their 30s, and the other three are older than 15 years and have normal serum creatinine. Four of the five patients have deafness but none have ocular abnormalities. Two have been transplanted and have not suffered from anti-GBM antibody nephritis. Men and women are equally affected. We have performed linkage analysis for chromosome 2 with the following markers: D2S279, COL4A3/4 DNTR, COL4A4 RFLP Hae III. RESULTS: We demonstrate that both families, one of them consanguineous, are linked to the COL4A3/4 locus. CONCLUSIONS: We can conclude that the only significant difference between the X-linked and the autosomal recessive forms of AS lies in the fact that in the latter females are as affected as males; thus the idea that autosomal recessive AS causes ESRD during childhood must be discarded. Other clinical features such as age of deafness or the presence of post-transplant anti-GBM antibody nephritis show no differences between the entities. Thus an accurate familial study is mandatory in patients with AS, as the identification of the different patterns of inheritance may cause a great difference in genetic counselling. Linkage analysis is the only effective molecular diagnosis that can be performed nowadays. 相似文献
20.
Friedhelm Hildebrandt Hans Gerd Nothwang Urs Vossmerbäumer Cornelia Springer Brigitte Strahm Bernd Hoppe Burkhard Keuth Arno Fuchshuber Uwe Querfeld Thomas J Neuhaus Matthias Brandis 《Pediatric nephrology (Berlin, Germany)》1998,12(1):16-19
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.
Received February 18, 1997; received in revised form and accepted June 26, 1997 相似文献