Enamel renal syndrome: A novel homozygous FAM20A founder mutation in 5 new Brazilian families.

Enamel renal syndrome (ERS) is a rare autosomal recessive disorder not fully characterized. Here we investigated ERS characteristics in 11 patients from 5 Brazilian families through clinical examination, imaging, renal ultrasonography, laboratory tests and DNA sequencing. The patients' age ranged from 6 to 25 years-old, and the presence of hypoplastic amelogenesis imperfecta, microdontia, intra-pulpal calcification, impacted posterior teeth with hyperplastic pericoronal follicles, gingival fibromatosis, ectopic calcifications on gingival and pericoronal tissues, and nephrocalcinosis were common findings to all patients. Only 4 patients showed abnormal laboratory tests (vitamin D, parathyroid hormone, phosphate, calcium). Intellectual disability and renal cysts were present in 2 patients each. Biallelic loss of function mutation in FAM20A gene, characterized by one base pair deletion in exon 11, resulting in a frameshift replacing a glutamine at codon 483 for a lysine and terminating at position 24 [NG_029809.1: c.1447delG; p.(Glu483Lysfs*24)], was detected in all patients, strongly suggesting a founder effect. Our results reinforce the distinct orofacial features of ERS, which are the clue for kidney examination and genetic testing. Early diagnosis is essential to minimize the deleterious effects related to ERS. Here we report the largest series of patients with ERS in a same population, and describe, for the first time, a founder mutation for FAM20A.

Glycine Amidinotransferase (GATM), Renal Fanconi Syndrome, and Kidney Failure.

Background For many patients with kidney failure, the cause and underlying defect remain unknown. Here, we describe a novel mechanism of a genetic order characterized by renal Fanconi syndrome and kidney failure.Methods We clinically and genetically characterized members of five families with autosomal dominant renal Fanconi syndrome and kidney failure. We performed genome-wide linkage analysis, sequencing, and expression studies in kidney biopsy specimens and renal cells along with knockout mouse studies and evaluations of mitochondrial morphology and function. Structural studies examined the effects of recognized mutations.Results The renal disease in these patients resulted from monoallelic mutations in the gene encoding glycine amidinotransferase (GATM), a renal proximal tubular enzyme in the creatine biosynthetic pathway that is otherwise associated with a recessive disorder of creatine deficiency. In silico analysis showed that the particular GATM mutations, identified in 28 members of the five families, create an additional interaction interface within the GATM protein and likely cause the linear aggregation of GATM observed in patient biopsy specimens and cultured proximal tubule cells. GATM aggregates-containing mitochondria were elongated and associated with increased ROS production, activation of the NLRP3 inflammasome, enhanced expression of the profibrotic cytokine IL-18, and increased cell death.Conclusions In this novel genetic disorder, fully penetrant heterozygous missense mutations in GATM trigger intramitochondrial fibrillary deposition of GATM and lead to elongated and abnormal mitochondria. We speculate that this renal proximal tubular mitochondrial pathology initiates a response from the inflammasome, with subsequent development of kidney fibrosis.

Polycystic Kidney Disease with Hyperinsulinemic Hypoglycemia Caused by a Promoter Mutation in Phosphomannomutase 2.

Hyperinsulinemic hypoglycemia (HI) and congenital polycystic kidney disease (PKD) are rare, genetically heterogeneous disorders. The co-occurrence of these disorders (HIPKD) in 17 children from 11 unrelated families suggested an unrecognized genetic disorder. Whole-genome linkage analysis in five informative families identified a single significant locus on chromosome 16p13.2 (logarithm of odds score 6.5). Sequencing of the coding regions of all linked genes failed to identify biallelic mutations. Instead, we found in all patients a promoter mutation (c.-167G>T) in the phosphomannomutase 2 gene (PMM2), either homozygous or in trans with PMM2 coding mutations. PMM2 encodes a key enzyme in N-glycosylation. Abnormal glycosylation has been associated with PKD, and we found that deglycosylation in cultured pancreatic ß cells altered insulin secretion. Recessive coding mutations in PMM2 cause congenital disorder of glycosylation type 1a (CDG1A), a devastating multisystem disorder with prominent neurologic involvement. Yet our patients did not exhibit the typical clinical or diagnostic features of CDG1A. In vitro, the PMM2 promoter mutation associated with decreased transcriptional activity in patient kidney cells and impaired binding of the transcription factor ZNF143. In silico analysis suggested an important role of ZNF143 for the formation of a chromatin loop including PMM2 We propose that the PMM2 promoter mutation alters tissue-specific chromatin loop formation, with consequent organ-specific deficiency of PMM2 leading to the restricted phenotype of HIPKD. Our findings extend the spectrum of genetic causes for both HI and PKD and provide insights into gene regulation and PMM2 pleiotropy.

Enamel-renal syndrome in 2 patients with a mutation in FAM20 A and atypical hypertrichosis and hearing loss phenotypes.

Enamel-renal syndrome (OMIM #204690) is an uncommon disorder characterized by amelogenesis imperfecta and nephrocalcinosis and is caused by mutations in FAM20 A. We report 2 patients with enamel-renal syndrome who exhibited the typical features of this syndrome and a homozygous nonsense mutation in the FAM20 A gene (c.406 C>T), genetically confirming the diagnosis. They also exhibited 2 undescribed clinical features, hypertrichosis and hearing loss. Alterations in genes frequently associated with nonsyndromic hearing loss in the Brazilian population, including connexin 26 (GJB2), connexin 30 (GJB6) and mitochondrial 12 S rRNA (m.A1555 G mutation), were not found. These results suggest a putative function of FAM20 A in the development of the inner ear and in the formation of hair. The presence of nephrocalcinosis is a risk factor for renal impairment, and it is important to perform regular renal monitoring in order to avoid renal failure.