An international cohort study of autosomal dominant tubulointerstitial kidney disease due to REN mutations identifies distinct clinical subtypes.

There have been few clinical or scientific reports of autosomal dominant tubulointerstitial kidney disease due to REN mutations (ADTKD-REN), limiting characterization. To further study this, we formed an international cohort characterizing 111 individuals from 30 families with both clinical and laboratory findings. Sixty-nine individuals had a REN mutation in the signal peptide region (signal group), 27 in the prosegment (prosegment group), and 15 in the mature renin peptide (mature group). Signal group patients were most severely affected, presenting at a mean age of 19.7 years, with the prosegment group presenting at 22.4 years, and the mature group at 37 years. Anemia was present in childhood in 91% in the signal group, 69% prosegment, and none of the mature group. REN signal peptide mutations reduced hydrophobicity of the signal peptide, which is necessary for recognition and translocation across the endoplasmic reticulum, leading to aberrant delivery of preprorenin into the cytoplasm. REN mutations in the prosegment led to deposition of prorenin and renin in the endoplasmic reticulum-Golgi intermediate compartment and decreased prorenin secretion. Mutations in mature renin led to deposition of the mutant prorenin in the endoplasmic reticulum, similar to patients with ADTKD-UMOD, with a rate of progression to end stage kidney disease (63.6 years) that was significantly slower vs. the signal (53.1 years) and prosegment groups (50.8 years) (significant hazard ratio 0.367). Thus, clinical and laboratory studies revealed subtypes of ADTKD-REN that are pathophysiologically, diagnostically, and clinically distinct.

A novel disease-causing mutation in the Renin gene in a Tunisian family with autosomal dominant tubulointerstitial kidney disease.

Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a rare group of disease that affect the tubules of the kidney. There are 4 known subtypes of ADTKD classified based on causative genes and clinical features. In our study, we aimed to identify the causative subtypes of ADTKD in a Tunisian ADTKD family (3 affected members), in whom standard nephrological diagnosis did not provide clear subtype of ADTKD, until genetic testing was performed. Sanger sequencing was performed for UMOD, HNF1ß and REN genes. Mutational analysis allowed us to detect a heterozygous mutation in the REN gene: c.1172C > G, (p.T391R) in exon 10. In silico analyses predicted that the novel likely pathogenic mutation affect protein stability and 3D structure. Our study highlights the importance of establishing a genetic diagnosis to identify the subtype of ADTKD for better patient care. To the best of our knowledge, we report here a first Tunisian ADTKD-REN family.

[Treacher-Collins syndrome: clinical and genetic aspects apropos of 4 cases of which 1 is familial]. / Le syndrome de Treacher Collins: aspects clinique et génétique à propos de 4 observations dont une familiale.

Treacher Collins syndrome was first mentioned by Thompson in 1847, and described by Treacher Collins in 1900, then it was called mandibulo-facial dysostosis and well defined by Franceschetti in 1949. It is a very rare affection occurring lin 50.000 live births, which includes facial and auricular anomalies leading to functional, morphological and psychological difficulties due to related handicaps. Treacher Collins syndrome is inherited as autosomal dominant pattern with a variable expressivity and incomplete penetrance of "TCOF1" gene localized at 5q31.3q32. Today the gene is well identified and several mutations have been reported. In this paper we report the case of 4 Tunisian unrelated girls with Treacher Collins syndrome. One of them was born from an affected father. Clinical diagnostic was performed between age 12 days and 2 years demonstrating the large dysmorphic expression. Main clinical features were present in all reported cases. Family at risk might have genetic counselling and probably prenatal diagnostic in some situations. Out of our observations, we gave genetic counselling and proposed ultrasound prenatal diagnosis for two families without molecular study.

Clinical, Molecular, and Computational Analysis in Patients With a Novel Double Mutation and a New Synonymous Variant in MeCP2: Report of the First Missense Mutation Within the AT-hook1 Cluster in Rett Syndrome.

Rett syndrome is an X-linked neurodevelopmental disorder, primarily caused by MECP2 mutations. In this study, clinical, molecular and bioinformatics analyses were performed in Rett patients to understand the relationship between MECP2 mutation type and the clinical severity. Two double MeCP2 mutations were detected: a novel one (p.G185 V in cis with p.R255X) in P1 and a known one (p.P179 S in cis with p.R255X) in P2. Besides, a novel synonymous mutation (c.807C>T; p.G269G), which could affect mRNA splicing, was identified in P3. The results from clinical severity analysis have shown that P1 was more severely affected than P2 with CSS being 35 and 14, respectively. Therefore, the phenotypic variability in P1 and P2 could be explained by the potential pathogenic effect of the RTT-causing missense mutation p.G185 V in the AT-hook1. In conclusion, clinical, molecular, and in silico investigations in the studied patients have been proven to be substantial for the genotype-phenotype correlation.