Fanconi Renotubular Syndrome 3

A number sign (#) is used with this entry because of evidence that Fanconi renotubular syndrome-3 (FRTS3) is caused by heterozygous mutation in the EHHADH gene (607037) on chromosome 3q27. One such family has been reported.

For a general phenotypic description and a discussion of genetic heterogeneity of Fanconi renotubular syndrome, see FRTS1 (134600).

Clinical Features

Tolaymat et al. (1992) reported a large African American family with Fanconi renal syndrome manifest as metabolic acidosis, hyperphosphaturia, hypercalciuria, aminoaciduria, glucosuria, and proteinuria. Several patients also had evidence of rickets, with short stature and genu varus. Members in 4 generations were probably affected, although the affected member of the first generation was not available for study. Eight affected individuals were recognized, with 1 instance of male-to-male transmission. Not all patients had the complete Fanconi syndrome; some did not have bone disease. None of the patients developed diabetes mellitus or renal failure.

Klootwijk et al. (2014) reported follow-up of the family reported by Tolaymat et al. (1992). Affected individuals had impaired growth and rickets, with femoral deformities, bowed legs, and loss of bone density from early childhood. There was impaired function of the proximal renal tubules, manifest by glucosuria, generalized aminoaciduria, phosphaturia, metabolic acidosis, and low molecular weight proteinuria. Although there was significant proteinuria, glomerular function was normal and none of the patients developed renal failure. The affected 74-year-old matriarch presented with slightly impaired kidney function, but had had normal kidney function at age 58 years.

Inheritance

The transmission pattern of Fanconi renotubular syndrome in the family reported by Tolaymat et al. (1992) was consistent with autosomal dominant inheritance.

Mapping

By genomewide linkage analysis of a family with autosomal dominant Fanconi renotubular syndrome, Klootwijk et al. (2014) found linkage to a region on chromosome 3q27 between markers D3S3583 and D3S2747 (maximum multipoint parametric lod score of 3.61).

Molecular Genetics

In affected members of a family with autosomal dominant Fanconi renotubular syndrome, originally reported by Tolaymat et al. (1992), Klootwijk et al. (2014) identified a heterozygous mutation in the EHHADH gene (E3K; 607037.0001). The mutation was found by genomewide linkage analysis followed by Sanger sequencing of candidate genes in the region. Transfection of the mutation into several cell lines, including a renal proximal tubular cell line, showed that the mutant protein localized to mitochondria as well as to peroxisomes, whereas wildtype EHHADH localized only to peroxisomes. Transfected renal tubular cells showed a defect in the transepithelial transport of fluids, with an inability to maintain fluid-filled domes in confluent monolayers, as well as a defect in luminal to basolateral transport of a glucose surrogate. These changes were associated with a defect in mitochondrial respiration and impaired ATP production. Mutant EHHADH coimmunoprecipitated with mitochondrial HADHA (600890) and HADHB (143450), which likely impaired mitochondrial function. These findings, combined with the lack of renal or mitochondrial dysfunction in Ehhadh-null mice, were consistent with a dominant-negative toxic effect of the mutant EHHADH protein rather than haploinsufficiency. Klootwijk et al. (2014) noted that proximal tubular cells use fatty acid oxidation as the predominant energy source, and that proper mitochondrial function is required for renal tubular reabsorption.