Heterozygous Mutations of FREM1 Are Associated with an Increased Risk of Isolated Metopic Craniosynostosis in Humans and Mice

The premature fusion of the paired frontal bones results in metopic craniosynostosis (MC) and gives rise to the clinical phenotype of trigonocephaly. Deletions of chromosome 9p22.3 are well described as a cause of MC with variably penetrant midface hypoplasia. In order to identify the gene responsible for the trigonocephaly component of the 9p22.3 syndrome, a cohort of 109 patients were assessed by high-resolution arrays and MLPA for copy number variations (CNVs) involving 9p22. Five CNVs involving FREM1, all of which were de novo variants, were identified by array-based analyses. The remaining 104 patients with MC were then subjected to targeted FREM1 gene re-sequencing, which identified 3 further mutant alleles, one of which was de novo. Consistent with a pathogenic role, mouse Frem1 mRNA and protein expression was demonstrated in the metopic suture as well as in the pericranium and dura mater. Micro-computed tomography based analyses of the mouse posterior frontal (PF) suture, the human metopic suture equivalent, revealed advanced fusion in all mice homozygous for either of two different Frem1 mutant alleles, while heterozygotes exhibited variably penetrant PF suture anomalies. Gene dosage-related penetrance of midfacial hypoplasia was also evident in the Frem1 mutants. These data suggest that CNVs and mutations involving FREM1 can be identified in a significant percentage of people with MC with or without midface hypoplasia. Furthermore, we present Frem1 mutant mice as the first bona fide mouse model of human metopic craniosynostosis and a new model for midfacial hypoplasia

Autophagy as a mechanism for anti-angiogenic therapy resistance

Autophagy is a lysosomal-dependent degradation process that is highly conserved and maintains cellular homeostasis by sequestering cytosolic material for degradation either non-specifically by non-selective autophagy, or targeting specific proteins aggregates by selective autophagy. Autophagy serves as a protective mechanism defending the cell from stressors and also plays an important role in enabling tumor cells to overcome harsh conditions arising in their microenvironment during growth as well as oxidative and non-oxidative injuries secondary to therapeutic stressors. Recently, autophagy has been implicated to cause tumor resistance to anti-angiogenic therapy, joining an existing literature implicating autophagy in cancer resistance to conventional DNA damaging chemotherapy and ionizing radiation. In this review, we discuss the role of angiogenesis in malignancy, mechanisms of resistance to anti-angiogenic therapy in general, the role of autophagy in driving malignancy, and the current literature in autophagy-mediated anti-angiogenic therapy resistance. Finally, we provide future insight into the current challenges of using autophagy inhibitors in the clinic and provides tips for future studies to focus on to effectively target autophagy in overcoming resistance to anti-angiogenic therapy

Role of a p53 polymorphism in the development of nonfunctional pituitary adenomas

Non-functional pituitary adenomas (NFPAs) are among the commonest intracranial neoplasms. While histologically benign, NFPAs sometimes become large enough to limit therapeutic options and reduce quality of life. Investigations of the molecular etiology of NFPAs have failed to identify prevalent genetic changes and, while a role for p53 has been suggested, TP53 gene alterations have yet to be described in NFPAs. We found that the polymorphism rs1042522:C > G in codon 72 of exon 4 of the TP53 gene, whose C variant produces a proline and is more common in most ethnicities, has a G variant producing an arginine in 79.8% of NFPAs (n = 42; p < 1.411 × 10-18 vs. 1000 Genomes database), causing patients to present a decade earlier with symptomatic NFPAs. In cultured NFPA cells, transfection with the rs1042522 G variant versus the C variant reduced expression of cell arrest gene p21 and increased proliferation. These findings suggest that this TP53 polymorphism influences NFPA growth

Systemic therapy for brain metastases

Metastases from cells outside of the central nervous system are the most common cancer found in the brain and are commonly associated with poor prognosis. Although cancer treatment is improving overall, central nervous system metastases are becoming more prevalent and require finesse to properly treat. Physicians must consider the biology of the primary tumor and the complex neurological environment that the metastasis resides in. This can be further complicated by the fact that the practice of cancer management is constantly evolving and therapy that works outside of the blood-brain barrier may not be effective inside of it. Therefore, this review seeks to update the reader on recent advancements made on the three most common sources of brain metastases: lung cancer, breast cancer, and melanoma. Each of these malignancies has been the subject of intriguing and novel avenues of therapy which are reviewed here

A variant associated with sagittal nonsyndromic craniosynostosis alters the regulatory function of a non‐coding element

Craniosynostosis presents either as a nonsyndromic congenital anomaly or as a finding in nearly 200 genetic syndromes. Our previous genome‐wide association study of sagittal nonsyndromic craniosynostosis identified associations with variants downstream from BMP2 and intronic in BBS9. Because no coding variants in BMP2 were identified, we hypothesized that conserved non‐coding regulatory elements may alter BMP2 expression. In order to identify and characterize noncoding regulatory elements near BMP2, two conserved noncoding regions near the associated region on chromosome 20 were tested for regulatory activity with a Renilla luciferase assay. For a 711 base pair noncoding fragment encompassing the most strongly associated variant, rs1884302, the luciferase assay showed that the risk allele (C) of rs1884302 drives higher expression of the reporter than the common allele (T). When this same DNA fragment was tested in zebrafish transgenesis studies, a strikingly different expression pattern of the green fluorescent reporter was observed depending on whether the transgenic fish had the risk (C) or the common (T) allele at rs1884302. The in vitro results suggest that altered BMP2 regulatory function at rs1884302 may contribute to the etiology of sagittal nonsyndromic craniosynostosis. The in vivo results indicate that differences in regulatory activity depend on the presence of a C or T allele at rs1884302.This article is published as Justice, Cristina M., Jinoh Kim, Sun‐Don Kim, Kyunhgho Kim, Garima Yagnik, Araceli Cuellar, Blake Carrington et al. "A variant associated with sagittal nonsyndromic craniosynostosis alters the regulatory function of a non‐coding element." American Journal of Medical Genetics Part A 173, no. 11 (2017): 2893-2897. DOI: 10.1002/ajmg.a.38392 .</p

ALX4 gain-of-function mutations in non-syndromic craniosynostosis

Craniosynostosis is the early fusion of one or more sutures of the infant skull and is a common defect occurring in approximately 1 of every 2,500 live births. Non-syndromic craniosynostosis accounts for approximately 80% of all cases and is thought to have strong genetic determinants that are yet to be identified. ALX4 is a homeodomain transcription factor with known involvement in osteoblast regulation. By direct sequencing of the ALX4 coding region in sagittal or sagittal-suture-involved non-syndromic craniosynostosis probands, we identified novel, nonsynonymous, familial variants in three of 203 individuals with NSC. Using dual-luciferase assay we show that two of these variants (V7F and K211E) confer a significant gain-of-function effect on ALX4. Our results suggest that ALX4 variants may have an impact on the genetic etiology of NSC

Aix-Marseille University student's professional integration

International audienceThis contribution presented at the Alma Laurea conference (Rome, June 6th) aimed to present Aix-Marseille University services and practices regarding the students career development