DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis.

Hypophosphatemia is a genetically heterogeneous disease. Here, we mapped an autosomal recessive form (designated ARHP) to chromosome 4q21 and identified homozygous mutations in DMP1 (dentin matrix protein 1), which encodes a non-collagenous bone matrix protein expressed in osteoblasts and osteocytes. Intact plasma levels of the phosphaturic protein FGF23 were clearly elevated in two of four affected individuals, providing a possible explanation for the phosphaturia and inappropriately normal 1,25(OH)2D levels and suggesting that DMP1 may regulate FGF23 expression.

Gitelman syndrome in Gypsy paediatric patients carrying the same intron 9 + 1 G>T mutation. Clinical features and impact on quality of life.

BACKGROUND: Gitelman syndrome is a primary tubular disorder causing hypokalaemic metabolic alkalosis with hypocalciuria. Its prevalence is high in Gypsies, who harbour an identical mutation, intron 9 + 1 G>T, in the SLC12A3 gene. METHODS: To better define the Gitelman syndrome in Gypsies, the clinical and biochemical features of 34 Spanish paediatric Gypsy patients were analysed. At diagnosis, symptoms, height and weight as well as serum and urinary biochemical data were collected. During a follow-up of 4.5 ± 2.4 years [X ± standard deviation (SD)], therapy, treatment compliance, symptoms, frequency of hospital admissions and, at the last visit, growth and biochemical work-up of 29 patients followed for at least 6 months were analysed. Quality of life items were also assessed by a questionnaire. RESULTS: Muscle cramps (41%) and asthenia (35%) were the most frequent presenting symptoms. Biochemical data at diagnosis were serum K 2.76 ± 0.46 mEq/L, serum Mg 1.32 ± 0.28 mg/dL, blood pH 7.45 ± 0.06, serum bicarbonate 28.2 ± 2.9 mEq/L, urinary calcium/creatinine ratio 0.03 ± 0.04 mg/mg, fractional K excretion 24.4 ± 17.1% and fractional Mg excretion 8.9 ± 8.3%. During follow-up, Mg and K supplements were prescribed to 79 and 86% of patients, respectively; compliance with treatment was good in 35%. Hospital admission rate was 0.03/patient/month. Muscle cramps were the symptom most often referred by the patients (45%) during the follow-up, and 71% of patients considered their health status as excellent or good. Twenty-one patients stated that their disease did not adversely interfere with their mood or social relationships. Height and weight of patients at diagnosis were -0.60 ± 1.17 and -0.49 ± 1.32 SD, respectively, and improved to -0.44 ± 1.28 (P < 0.05) and 0.18 ± 1.79 SD (P < 0.01) at the last visit. CONCLUSIONS: Gypsy children with Gitelman syndrome mostly exhibit muscle symptoms and asthenia although the disease is not particularly severe in this ethnic group. Body growth improves with treatment and close follow-up.

Quality of life of adolescents with end-stage renal disease and kidney transplant.

The health-related quality of life (HRQOL) of adolescents with end-stage renal disease (ESRD) is an important marker of disease burden. Our aims were to investigate HRQOL in a group of children and adolescents with ESRD and to compare them with the reference population norms. Ours was a cross-sectional study of 81 patients aged 10 years to 21 years with ESRD (68 with kidney transplants and 13 on dialysis) at five Spanish paediatric nephrology centres. HRQOL was investigated with the Spanish version of the child health and illness profile, adolescent edition (CHIP-AE). Clinical variables such as underlying diagnosis, number of rejection episodes, pre-emptive transplantation, anaemia and height were also analysed. No differences were found between patients with kidney transplants and their healthy peers in any domain or sub-domain of CHIP-AE. The group on dialysis scored lower than healthy controls and patients with transplants for satisfaction with health. Discomfort was higher in patients with transplants who had suffered one rejection episode. Physical discomfort was increased in anaemic patients with transplants. Short patients scored less in the satisfaction domain, with lower self-esteem and lower satisfaction with health. Adolescents with kidney transplants had better satisfaction with health than the group on dialysis, which matched the level of a healthy population. Further long-term prospective research is warranted.

Claudin-19 mutations and clinical phenotype in Spanish patients with familial hypomagnesemia with hypercalciuria and nephrocalcinosis.

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is an autosomal recessive tubular disorder characterized by excessive renal magnesium and calcium excretion and chronic kidney failure. This rare disease is caused by mutations in the CLDN16 and CLDN19 genes. These genes encode the tight junction proteins claudin-16 and claudin-19, respectively, which regulate the paracellular ion reabsorption in the kidney. Patients with mutations in the CLDN19 gene also present severe visual impairment. Our goals in this study were to examine the clinical characteristics of a large cohort of Spanish patients with this disorder and to identify the disease causing mutations. We included a total of 31 patients belonging to 27 unrelated families and studied renal and ocular manifestations. We then analyzed by direct DNA sequencing the coding regions of CLDN16 and CLDN19 genes in these patients. Bioinformatic tools were used to predict the consequences of mutations. Clinical evaluation showed ocular defects in 87% of patients, including mainly myopia, nystagmus and macular colobomata. Twenty two percent of patients underwent renal transplantation and impaired renal function was observed in another 61% of patients. Results of the genetic analysis revealed CLDN19 mutations in all patients confirming the clinical diagnosis. The majority of patients exhibited the previously described p.G20D mutation. Haplotype analysis using three microsatellite markers showed a founder effect for this recurrent mutation in our cohort. We also identified four new pathogenic mutations in CLDN19, p.G122R, p.I41T, p.G75C and p.G75S. A strategy based on microsequencing was designed to facilitate the genetic diagnosis of this disease. Our data indicate that patients with CLDN19 mutations have a high risk of progression to chronic renal disease.

A new mutation (intron 9 +1 G>T) in the SLC12A3 gene is linked to Gitelman syndrome in Gypsies.

BACKGROUND: Gitel syndrome is an inherited tubular disorder characterized by metabolic alkalosis, hypokalemia, and hypomagnesemia of renal origin and hypocalciuria. The majority of patients with Gitelman syndrome carry inactivating mutations in the SLC12A3 gene encoding the sodium-chloride cotransporter located in the distal convoluted tubule. The purpose of this study was to investigate the underlying mutation in Gitelman syndrome patients of Gypsy race from different geographic origin. METHODS: Twenty Gypsy patients with clinical and biochemical features of Gitelman syndrome were investigated by mutational analysis. The patients belonged to 12 unrelated Gypsy families living in four different European countries. The parents and unaffected siblings of each patient, as well as the DNA of a population of 200 healthy control patients, were also analyzed. RESULTS: All patients were homozygous for the same splice site mutation, guanine to thymine in the first position of intron 9 of SLC12A3 gene. This mutation was not found in the control population. Parents were heterozygous for the mutation. Despite sharing a common mutation, the clinical manifestations of the syndrome in the patients varied from lack of symptoms in six children to severe growth retardation in four. CONCLUSION: Demonstration of a novel point mutation within the SLC12A3 gene in our cohort of Gypsy families with Gitelman syndrome is highly suggestive of a founder effect. This finding will facilitate the identification of the genetic defect in further cases of Gitelman syndrome among the Gypsy population. Our study represents the largest series ever published of patients with Gitelman syndrome having the same underlying mutation, and supports the lack of correlation between genotype and clinical phenotype in this disease.

Novel truncating mutations in the ClC-5 chloride channel gene in patients with Dent's disease.

BACKGROUND: Dent's disease is characterized by low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, rickets and eventual renal failure. The disease is caused by mutations in the X-linked chloride channel CLCN5 gene, which encodes a 746-amino-acid protein expressed in renal tubules. These mutations have been reported in unrelated families from the UK, USA, Japan and other countries. We were interested in identifying additional mutations in the CLCN5 coding region of Spanish patients with Dent's disease. METHODS: Five patients from three unrelated Spanish families were studied. Leukocyte genomic DNA from patients and their relatives was used with CLCN5-specific primers for polymerase chain reaction amplification of the coding region and exon-intron boundaries. Amplified products were analysed by single-strand conformational polymorphism analysis, DNA sequencing and restriction enzyme analysis. RESULTS: Low-molecular-weight proteinuria and hypercalciuria were detected in all the patients, nephrocalcinosis in two patients, and rickets or osteopenia in three patients. We identified three new CLCN5 mutations consisting of two nonsense mutations, Leu433Stop and Arg718Stop, and an insertional frameshift mutation, 65insT, which results in a stop at codon 98. These three mutations predict truncated ClC-5 proteins that, respectively, lack 314, 649 and 28 amino acids at the carboxy terminus, and are likely to result in loss of function. These mutations were shown to co-segregate with the disease in each of the three families. CONCLUSIONS: Our study is the first to characterize mutations in the CLCN5 gene in Spanish patients with Dent's disease and expands the spectrum of CLCN5 mutations associated with this disease.

Renin-angiotensin system polymorphisms and renal scarring.

The purpose of the study was to determine whether DNA polymorphisms at the renin-angiotensin-aldosterone (RAS) genes were associated with evolution to renal scar formation and, consequently, with reflux nephropathy (RN) in patients with vesicoureteral reflux (VUR). Some authors have suggested that the DD genotype of the angiotensin-converting enzyme (ACE) gene would be an adverse renal prognosis factor. We recruited 246 patients (aged 3 months to 22 years) from four Spanish hospitals. These included 69 patients with VUR, 110 with RN (determined by absence/presence of renal scarring on dimercaptosuccinc acid scan), 27 with chronic renal failure due to RN, and 40 patients (control group) with urinary tract infection and normal findings on renal ultrasonography and voiding cystoureterogram. The ACE I/D, angiotensin II type 1 receptor AT1 A1166C, angiotensin II type 2 receptor A3123C AT2, and angiotensinogen AGT M235T polymorphisms were determined on the basis of polymerase chain reaction amplification. ACE serum levels were determined by spectrophotometric methods. We found no statistical differences in the distribution of RAS polymorphisms between the different groups. The ACE D allele was linked to higher ACE serum levels. We found no association between ACE I/D polymorphism and presence of hypertension, proteinuria, grade of VUR, or unilateral/bilateral VUR. Patients with the DD genotype had a lower incidence of febrile urinary tract infection as a first symptom of VUR/RN (P<0.05). We conclude that genetic polymorphisms of RAS components are not independent prognostic indicators of renal scarring in patients with VUR.