Autosomal-dominant medullary cystic kidney disease type 1: Clinical and molecular findings in six large Cypriot families

Stavrou, Christoforos; Koptides, Michael; Tombazos, Christos; Psara, Evlalia; Patsias, Charalambos; Zouvani, Ioanna; Kyriacou, Kyriacos; Hildebrandt, Friedhelm; Christofides, Tasos C.; Pierides, Alkis; Deltas, Constantinos

doi:10.1111/j.1523-1755.2002.kid581.x

Cited by 65 publications

(30 citation statements)

References 34 publications

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“…All patients are from the area of Pafos near the west coast, geographically clustered in a triangle of three neighboring villages. 44 For a recessive disorder, a classic example is the CFTR mutation F508del, with a carrier frequency of 1:14 in the village of Athienou, near Nicosia, the CLINICAL RESEARCH www.jasn.org capital 36 (for an extensive description of founder effects in Cyprus, see Deltas 38 ).…”

Section: Mutation Screening Dna Sequencing and Founder Effectsmentioning

confidence: 99%

COL4A3/COL4A4 Mutations Producing Focal Segmental Glomerulosclerosis and Renal Failure in Thin Basement Membrane Nephropathy

Voskarides¹,

Damianou²,

Neocleous³

et al. 2007

Journal of the American Society of Nephrology

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178

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Mutations in the COL4A3/COL4A4 genes of type IV collagen have been found in ϳ40% of cases of thin basement membrane nephropathy, which is characterized by microscopic hematuria and is classically thought to cause proteinuria and chronic renal failure rarely. Here we report our observations of 116 subjects from 13 Cypriot families clinically affected with thin basement membrane nephropathy. These families first came to our attention because they segregated microscopic hematuria, mild proteinuria, and variable degrees of renal impairment, but a dual diagnosis of focal segmental glomerulosclerosis (FSGS) and thin basement membrane nephropathy was made in 20 biopsied cases. Molecular studies identified founder mutations in both COL4A3 and COL4A4 genes in 10 families. None of 82 heterozygous patients had any extrarenal manifestations, supporting the diagnosis of thin basement membrane nephropathy. During follow-up of up to three decades, 31 of these 82 patients (37.8%) developed chronic renal failure and 16 (19.5%) reached end-stage renal disease. Mutations G1334E and G871C were detected in seven and three families, respectively, and were probably introduced by founders. We conclude that these particular COL4A3/COL4A4 mutations either predispose some patients to FSGS and chronic renal failure, or that thin basement membrane nephropathy sometimes coexists with another genetic modifier that is responsible for FSGS and progressive renal failure. The findings presented here do not justify the labelling of thin basement membrane nephropathy as a benign condition with excellent prognosis.

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Section: Mutation Screening Dna Sequencing and Founder Effectsmentioning

confidence: 99%

COL4A3/COL4A4 Mutations Producing Focal Segmental Glomerulosclerosis and Renal Failure in Thin Basement Membrane Nephropathy

Voskarides¹,

Damianou²,

Neocleous³

et al. 2007

Journal of the American Society of Nephrology

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189

178

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“…Identification of the MUC1 etiology for MCKD1 permits us, for the first time, to provide a clinical characterization of individuals with known MCKD1, including individuals who have mild disease and in whom diagnosis could not be ascertained in the past. The only prior detailed clinical characterizations of this condition were in six families from Cyprus (11) and one Native American family (12) linked to chromosome 1. In this manuscript, we describe 24 families with an MUC1 mutation.…”

Section: Introductionmentioning

confidence: 99%

Variable Clinical Presentation of an MUC1 Mutation Causing Medullary Cystic Kidney Disease Type 1

Bleyer

Kmoch

Antignac

et al. 2014

Clinical Journal of the American Society of Nephrology

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Background and objectives The genetic cause of medullary cystic kidney disease type 1 was recently identified as a cytosine insertion in the variable number of tandem repeat region of MUC1 encoding mucoprotein-1 (MUC1), a protein that is present in skin, breast, and lung tissue, the gastrointestinal tract, and the distal tubules of the kidney. The purpose of this investigation was to analyze the clinical characteristics of families and individuals with this mutation.Design, setting, participants, & measurements Families with autosomal dominant interstitial kidney disease were referred for genetic analysis over a 14-year period. Families without UMOD or REN mutations prospectively underwent genotyping for the presence of the MUC1 mutation. Clinical characteristics were retrospectively evaluated in individuals with the MUC1 mutation and historically affected individuals (persons who were both related to genetically affected individuals in such a way that ensured that they could be genetically affected and had a history of CKD stage IV or kidney failure resulting in death, dialysis, or transplantation).Results Twenty-four families were identified with the MUC1 mutation. Of 186 family members undergoing MUC1 mutational analysis, the mutation was identified in 95 individuals, 91 individuals did not have the mutation, and111 individuals were identified as historically affected. Individuals with the MUC1 mutation suffered from chronic kidney failure with a widely variable age of onset of end stage kidney disease ranging from 16 to .80 years. Urinalyses revealed minimal protein and no blood. Ultrasounds of 35 individuals showed no medullary cysts. There were no clinical manifestations of the MUC1 mutation detected in the breasts, skin, respiratory system, or gastrointestinal tract.Conclusion MUC1 mutation results in progressive chronic kidney failure with a bland urinary sediment. The age of onset of end stage kidney disease is highly variable, suggesting that gene-gene or gene-environment interactions contribute to phenotypic variability.

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“…There are other forms of autosomal dominant interstitial kidney disease with similar clinical manifestations that are either linked to another area of chromosome 1 or not linked to one of these areas. 9,10 MCKD 1 MCKD 1 demonstrates linkage to chromosome 1q21 in a number of reports, [5][6][7]11 but only a few studies provide details of the clinical picture. The predominant and perhaps only clinical characteristic is insidious progression to kidney failure, with most other clinical manifestations being secondary to renal failure per se.…”

mentioning

confidence: 99%

“…The predominant and perhaps only clinical characteristic is insidious progression to kidney failure, with most other clinical manifestations being secondary to renal failure per se. 2,6 Age at onset of clinical renal failure is variable within and between families. Renal insufficiency may first be noted in the teenage years, although some affected individuals have relatively well-preserved renal function into the fourth decade of life.…”

mentioning

confidence: 99%

“…The rate of progression to renal failure is poorly documented, because many family members are initially identified late in the course of their disease. In the best characterized families, the average age of onset of ESRD is approximately 50 yr, ranging from 36 to 80 yr. 2,6 Hypertension occurs but is likely related to underlying renal failure. Hypertension was particularly severe in one family whose disease was linked to 1q21.…”

mentioning

confidence: 99%

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Improving the Recognition of Hereditary Interstitial Kidney Disease

Bleyer

2009

Journal of the American Society of Nephrology

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Autosomal-dominant medullary cystic kidney disease type 1: Clinical and molecular findings in six large Cypriot families

Cited by 65 publications

References 34 publications

COL4A3/COL4A4 Mutations Producing Focal Segmental Glomerulosclerosis and Renal Failure in Thin Basement Membrane Nephropathy

COL4A3/COL4A4 Mutations Producing Focal Segmental Glomerulosclerosis and Renal Failure in Thin Basement Membrane Nephropathy

Variable Clinical Presentation of an MUC1 Mutation Causing Medullary Cystic Kidney Disease Type 1

Improving the Recognition of Hereditary Interstitial Kidney Disease

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