RESUMO
Hereditary distal renal tubular acidosis (dRTA) is a rare genetic disease that is caused by mutations in SLC4A1, ATP6V1B1, or ATP6V0A4. However, there are many families with hereditary dRTA in whom the disease-causing genes are unknown. Accordingly, we performed whole exome sequencing and genetic studies of the members of a family with autosomal recessive dRTA of an unknown genetic etiology. Here, we report compound heterozygous pathogenic variations in tryptophan-aspartate repeat domain 72 (WDR72) (c.1777A>G [p.R593G] and c.2522T>A [p.L841Q]) in three affected siblings of a family with dRTA. Both variants segregated with dRTA in the family and were not observed in normal control subjects. Homologous modeling and in silico mutagenesis indicated that R593G and L841Q alter the H-bond formations in the nearby residues, affecting the WDR72 protein structure. All these evidences indicate that the identified WDR72 variations were probably to have caused hereditary dRTA in the reported family. In addition, homozygous nonsense mutation (c.2686C>T [p.R896X]) was identified in another family, strongly supporting the causal role of WDR72 in dRTA. Based on our literature review, WDR72 mutations associated with dRTA have not been previously described. This is the first identification of pathogenic variations in WDR72 as a cause of hereditary dRTA.
Assuntos
Acidose Tubular Renal/diagnóstico , Acidose Tubular Renal/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Mutação , Proteínas/genética , Adolescente , Adulto , Sequência de Aminoácidos , Biomarcadores , Estudos de Casos e Controles , Criança , Biologia Computacional/métodos , Análise Mutacional de DNA , Feminino , Estudos de Associação Genética/métodos , Genótipo , Humanos , Masculino , Modelos Moleculares , Linhagem , Fenótipo , Conformação Proteica , Proteínas/química , Sequenciamento do Exoma , Adulto JovemRESUMO
BACKGROUND: Distal renal tubular acidosis (dRTA) caused by mutations of the SLC4A1 gene encoding the erythroid and kidney isoforms of anion exchanger 1 (AE1 or band 3) has a high prevalence in some tropical countries, particularly Thailand, Malaysia, the Philippines and Papua New Guinea (PNG). Here the disease is almost invariably recessive and can result from either homozygous or compound heterozygous SLC4A1 mutations. METHODS: We have collected and reviewed our own and published data on tropical dRTA to provide a comprehensive series of clinical and epidemiological studies in 78 patients. RESULTS: Eight responsible SLC4A1 mutations have been described so far, four of them affecting multiple unrelated families. With the exception of the mutation causing South-East Asian ovalocytosis (SAO), none of these mutations has been reported outside the tropics, where dRTA caused by SLC4A1 mutations is much rarer and almost always dominant, resulting from mutations that are quite different from those found in the tropics. SLC4A1 mutations, including those causing dRTA, may cause morphological red cell changes, often with excess haemolysis. In dRTA, these red cell changes are usually clinically recessive and not present in heterozygotes. The high tropical prevalence of dRTA caused by SLC4A1 mutations is currently unexplained. CONCLUSION: A hypothesis suggesting that changes in red cell metabolism caused by these mutations might protect against malaria is put forward to explain the phenomenon, and a possible mechanism for this effect is proposed.
Assuntos
Acidose Tubular Renal/genética , Proteína 1 de Troca de Ânion do Eritrócito/genética , Mutação/genética , Acidose Tubular Renal/epidemiologia , Proteína 1 de Troca de Ânion do Eritrócito/metabolismo , Ásia/epidemiologia , Criança , Pré-Escolar , Consanguinidade , Eritrócitos Anormais/metabolismo , Eritrócitos Anormais/fisiologia , Feminino , Doenças Hematológicas/epidemiologia , Doenças Hematológicas/genética , Heterozigoto , Homozigoto , Humanos , Lactente , Malária/genética , Masculino , Papua Nova Guiné/epidemiologia , Linhagem , Fenótipo , Filipinas/epidemiologia , Tailândia/epidemiologiaRESUMO
In the cyclosporine era, reports on pediatric kidney transplant (KTx) patients with obstructive and reflux uropathy are limited by small numbers, short follow-up, and/or lack of control groups. Our single-center study evaluated long-term outcomes (patient and graft survival, urinary tract infections [UTIs], urologic complications) in a large cohort of KTx recipients (<20 years old). We matched our 117 study patients with obstructive and reflux uropathy with 117 controls whose KTx was needed for other reasons; all 234 underwent their KTx between April 25, 1984, and October 23, 2002. The mean age was 8.0 +/- 6.2 years; mean follow-up, 133 +/- 67 months. The urologic complication rate was higher in study patients (43%) than in controls (11%) (p < 0.0001), as was the UTI rate (45% vs. 2%; p < 0.0001). The metabolic acidosis and UTI rates were higher in study patients who did (vs. did not) undergo bladder augmentation (p < 0.0001). We found no significant difference between study patients and controls in patient or graft survival, acute or chronic rejection, or mean estimated glomerular filtration rates. Unique to our study is the finding of higher metabolic acidosis and UTI rates in study patients who underwent bladder augmentation.