Few cerebro-renal syndromes have been described to date. Perez et al. identify a novel autosomal recessive cerebro-renal syndrome in a consanguineous Bedouin kindred, caused by a mutation in SLC30A9. The mutation disrupts the role of SLC30A9 in Zn2+ transport, leading to impaired regulation of cytosolic zinc homeostasis.

Pelizaeus-Merzbacher disease is an X-linked hypomyelinating leukodystrophy caused by PLP1 mutations. A similar autosomal-recessive phenotype, Pelizaeus-Merzbacher-like disease (PMLD), has been shown to be caused by homozygous mutations in GJC2 or HSPD1. We report a consanguineous Israeli Bedouin kindred with clinical and radiological findings compatible with PMLD in which linkage to PLP1, GJC2, and HSPD1 was excluded. Through genome-wide homozygosity mapping and mutation analysis, we demonstrated in all affected individuals a homozygous frameshift mutation that fully abrogates the main active domain of AIMP1, encoding ARS-interacting multifunctional protein 1. The mutation fully segregates with the disease-associated phenotype and was not found in 250 Bedouin controls. Our findings are in line with the previously demonstrated inability of mutant mice lacking the AIMP1/p43 ortholog to maintain axon integrity in the central and peripheral neural system.

Siblings of non-consanguineous Jewish-Ethiopian ancestry presented with congenital axial hypotonia, weakness of the abducens nerve, psychomotor developmental delay with brain ventriculomegaly, variable thinning of corpus callosum and cardiac septal defects. Homozygosity mapping identified a single disease-associated locus of 3.5 Mb on chromosome 3. Studies of a Bedouin consanguineous kindred affected with a similar recessive phenotype identified a single disease-associated 18 Mb homozygosity locus encompassing the entire 3.5 Mb locus. Whole exome sequencing demonstrated only two homozygous mutations within a shared identical haplotype of 0.6 Mb, common to both Bedouin and Ethiopian affected individuals, suggesting an ancient common founder. Only one of the mutations segregated as expected in both kindreds and was not found in Bedouin and Jewish-Ethiopian controls: c.1404A>G, p.[*468Trpext*6] in CCDC174. We showed that CCDC174 is ubiquitous, restricted to the cell nucleus and co-localized with EIF4A3. In fact, yeast-two-hybrid assay demonstrated interaction of CCDC174 with EIF4A3, a component of exon junction complex. Knockdown of the CCDC174 ortholog in Xenopus laevis embryos resulted in poor neural fold closure at the neurula stage with later embryonic lethality. Knockdown embryos exhibited a sharp reduction in expression of n-tubulin, a marker for differentiating primary neurons, and of hindbrain markers krox20 and hoxb3. The Xenopus phenotype could be rescued by the human normal, yet not the mutant CCDC174 transcripts. Moreover, overexpression of mutant but not normal CCDC174 in neuroblastoma cells caused rapid apoptosis. In line with the hypotonia phenotype, the CCDC174 mutation caused depletion of RYR1 and marked myopathic changes in skeletal muscle of affected individuals.

Topoisomerase I (topo I) is an essential nuclear enzyme involved in virtually all aspects of gene expression, and is the target of the anti-cancer drugs- camptothecin (CPT) and its derivatives. Improvement of the survival rates of young women with cancer has led to the consideration of the effects of long-term chemotherapy on their fertility. The effect of anticancer drugs on ovarian function was previously investigated; however, no reports are available concerning their effect on the endometrium, whose integrity is an important factor in embryo implantation. Here we used a rat animal model to investigate the expression and activity of topo I in the various physiologic phases of the endometrium and the influence of CPT on its integrity and receptivity. The results show, for the first time, that the endometrial topo I level and activity are influenced by the physiologic phases of the endometrium (estrous cycle) and correlate with the estrogen blood concentration. Treatment with the anti-cancer drug CPT caused histological disruption of the endometrium and deleterious effect on its cyclicity. Moreover, CPT treatment significantly reduced the implantation rate of embryos, suggesting alteration in the receptivity of the endometrium. These results suggest that topo I is important for maintaining the normal physiologic cyclicity and functionality of the endometrium in rats. Anti-cancer agents that target topo I severely impair estrous cycle progression and endometrial integrity and receptivity, emphasizing the importance of addressing the effect of chemotherapy on the endometrial functionality.

in such early-onset forms of neurodegenerative diseases. 7 In this respect, it would have been interesting if the authors had provided neurophysiological analyses, particularly on the peripheral nerve functions of their patients.The clinical and MRI presentation of the AIMP1 mutated patients reported in this paper is in agreement with the important role of AIMP1 in regulating neurofilament and maintaining axon-cytoskeleton integrity, and not as a primitive disorder of the myelination. Nevertheless, in such a highly inbred population, we cannot rule out the possibility of another mutated gene implicated in the etiology of the complex phenotype. 8 In conclusion, the genetician and neurologist cannot consider AIMP1 as a candidate gene for PMLD mutations. Patients with early severe neurodegenerative disorder involving axonal functions and myelin development seem presently more appropriate for AIMP1 mutation screening.