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  • 总部: 泰国曼谷市巴吞汪区仑披尼分区 普勒吉路齐隆巷5号.
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Alternative titles; symbolsHYPERURICEMIC NEPHROPATHY, FAMILIAL JUVENILE, 4; HNFJ4A number sign (#) is used with this entry because of evidence that autosomal dom...

Alternative titles; symbols


A number sign (#) is used with this entry because of evidence that autosomal dominant tubulointerstitial kidney disease-5 (ADTKD5) is caused by heterozygous mutation in the SEC61A1 gene (609213) on chromosome 3q21.

▼ Description
Autosomal dominant tubulointerstitial kidney disease-5 (ADTKD5) is characterized by the onset of progressive chronic renal disease in the first decades of life. Mild hyperuricemia may be present, but gout, hypertension, and proteinuria are usually absent. The disease may be associated with anemia or neutropenia. Some patients may have additional findings, including poor overall growth and impaired cognitive function. Renal biopsy shows tubulointerstitial abnormalities with atrophic tubules and fibrosis; secondary glomerular abnormalities and simple cysts may also be present (summary by Bolar et al., 2016).

For a discussion of genetic heterogeneity and revised nomenclature of ADTKD, see ADTKD1 (162000).

▼ Clinical Features
Bolar et al. (2016) reported a large 3-generation family in which 7 individuals had progressive chronic kidney disease associated with congenital anemia and intrauterine and postnatal growth retardation. Laboratory studies showed anemia that was responsive to erythropoietin, elevated serum creatinine levels, and mild hyperuricemia. Kidney biopsies from 2 patients showed multiple small foci of tubulointerstitial lesions, including clusters of atrophic tubules with thickened tubular basement membranes, and interstitial fibrosis. There was cystic dilatation of Bowman spaces with collapsed or rudimentary glomerular tufts, focal glomerular sclerosis, arterial intimal thickening, and luminal narrowing of blood vessels. Additional variable findings included cleft palate or bifid uvula (2 patients), velopharyngeal insufficiency (1 patient), preaxial polydactyly (1 patient), and mild cognitive impairment (4 patients). Hypertension, hematuria, proteinuria, neutropenia, and gout were not present in these patients. A father and daughter from a second family had a similar renal disorder with some differences from the first family. Both patients had congenital anemia, neutropenia, gout in the second decade of life, and chronic kidney disease. Both had recurrent infections in childhood that resolved around age 12 years. Renal ultrasound showed hyperechogenic parenchyma in the daughter and multiple simple cysts in the father. Both had increased serum uric acid and decreased urinary uromodulin (UMOD; 191845), but no proteinuria. The patients had normal growth and development. Renal biopsy was not performed.

▼ Inheritance
The transmission pattern of ADTKD5 in the families reported by Bolar et al. (2016) was consistent with autosomal dominant inheritance.

▼ Molecular Genetics
In affected members of 2 unrelated families with ADTKD5, Bolar et al. (2016) identified 2 different heterozygous missense mutations in the SEC61A1 gene (T185A, 609213.0001 and V67G, 609213.0002). The mutation in the first family was found by a combination of linkage analysis and whole-exome sequencing, whereas the mutation in the second family was found by custom gene panel sequencing of 46 unrelated probands with a renal disorder; the mutations segregated with the disorder in both families. The mutations affected the selectivity and permeability of the pore of the translocon channel. Transfection of the mutations into HEK293 cells resulted in decreased protein levels compared to wildtype, and both mutant proteins formed intracellular clumps that were localized in the endoplasmic reticulum and partially in the Golgi apparatus. The findings suggested that the mutant proteins were subjected to endoplasmic-reticulum-associated degradation (ERAD) and increased ER stress. The mutant T185A protein was unable to rescue the tubular atrophy phenotype in zebrafish embryos with morpholino knockdown of the sec61a1 ortholog, suggesting that this mutation results in a complete loss of function. The V67G protein showed partial rescue of the zebrafish phenotype. The findings suggested that SEC61A1 is necessary for proper tubular organization of the nephron, and that the disorder results from protein translocation defects across the endoplasmic reticulum membrane.

▼ Animal Model
Bolar et al. (2016) found that morpholino knockdown of the sec61a1 ortholog in zebrafish embryos resulted in increased frequency of absence or decreased convolution of the pronephric tubules compared to wildtype, consistent with tubular atrophy.

Tags: 3q21.3