Search

MPZL2‐related hearing loss is a rare form of autosomal recessive hearing loss characterized by progressive, mild sloping to severe sensorineural hearing loss. Thirty‐five previously reported patients had biallelic truncating variants in MPZL2, with the exception of one patient with a missense variant of uncertain significance and a truncating variant. Here, we describe the clinical characteristics and genotypes of five patients from four families with confirmed MPZL2‐related hearing loss. A rare missense likely pathogenic variant [NM_005797.4(MPZL2):c.280C>T,p.(Arg94Trp)] located in exon 3 was confirmed to be in trans with a recurrent pathogenic truncating variant that segregated with hearing loss in three of the patients from two unrelated families. This is the first recurrent likely pathogenic missense variant identified in MPZL2. Apparently milder or later‐onset hearing loss associated with rare missense variants in MPZL2 indicates that some missense variants in this gene may cause a milder phenotype than that resulting from homozygous or compound heterozygous truncating variants. This study, along with the identification of truncating loss of function and missense MPZL2 variants in several diverse populations, suggests that MPZL2‐related hearing loss may be more common than previously appreciated and demonstrates the need for MPZL2 inclusion in hearing loss testing panels. [ABSTRACT FROM AUTHOR]

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2007.04.035 Byline: Elena N. Pugacheva (1), Sandra A. Jablonski (1), Tiffiney R. Hartman (2), Elizabeth P. Henske (2), Erica A. Golemis (1) Keywords: CELLBIO; CELLCYCLE; SIGNALING Abstract: The mammalian cilium protrudes from the apical/lumenal surface of polarized cells and acts as a sensor of environmental cues. Numerous developmental disorders and pathological conditions have been shown to arise from defects in cilia-associated signaling proteins. Despite mounting evidence that cilia are essential sites for coordination of cell signaling, little is known about the cellular mechanisms controlling their formation and disassembly. Here, we show that interactions between the prometastatic scaffolding protein HEF1/Cas-L/NEDD9 and the oncogenic Aurora A (AurA) kinase at the basal body of cilia causes phosphorylation and activation of HDAC6, a tubulin deacetylase, promoting ciliary disassembly. We show that this pathway is both necessary and sufficient for ciliary resorption and that it constitutes an unexpected nonmitotic activity of AurA in vertebrates. Moreover, we demonstrate that small molecule inhibitors of AurA and HDAC6 selectively stabilize cilia from regulated resorption cues, suggesting a novel mode of action for these clinical agents. Author Affiliation: (1) Division of Basic Science, Fox Chase Cancer Center, Philadelphia, PA 19111, USA (2) Division of Medical Science, Fox Chase Cancer Center, Philadelphia, PA 19111, USA Article History: Received 6 October 2006; Revised 2 February 2007; Accepted 9 April 2007 Article Note: (miscellaneous) Published: June 28, 2007

Current National Comprehensive Cancer Network (NCCN) screening guidelines recommend genetic risk evaluation for all individuals diagnosed with renal cell carcinoma (RCC) ≤ 46 years of age. The identification of patients with hereditary RCC due to a germline pathogenic variant in a renal cancer risk gene is important for directing appropriate care, including clinical management and genetic counseling. Although the distribution of pathogenic variants in cancer susceptibility genes has been evaluated in referral-based cohorts of individuals diagnosed with RCC, this distribution has not been studied in population-based cohorts. To ascertain the frequency of germline mutations in this patient population, we analyzed research whole exome sequencing data for 21 genes in which mutations are associated with susceptibility to renal cancer in 60 individuals diagnosed with RCC ≤ 46 years recruited from the Penn Medicine BioBank. Analysis identified 4,223 variants in the study;individuals, six of which were classified as pathogenic or likely pathogenic (P/LP). Each was identified in a single individual, four with a pathogenic variant in the VHL gene, one in the CHEK2 gene, and one in the PMS2 gene. Three of the individuals with a VHL pathogenic variant had previous diagnostic clinical testing. One individual had a family history of RCC associated with Von Hippel-Lindau syndrome and no prior genetic testing. Only two individuals were found to have a pathogenic variant not been previously identified by clinical testing. CHEK2 c.1100del and PMS2 c.2186_2187del (1.67%). Our analysis suggests that the age at diagnosis (≤ 46 years) as an indication for offering RCC genetic testing should be reevaluated given the low diagnostic yield of identifying individuals with an unknown P/LP variant based on this criterion alone.;The identification of an inherited P/LP variant in renal cancer susceptibility genes can facilitate prevention strategies for RCC, including, but not limited to, cancer surveillance, genetic testing of family members, and education and awareness of non-RCC tumor risks. Further research is needed to fill gaps in the literature and help establish more comprehensive recommendations for the care and management of this patient population. [ABSTRACT FROM AUTHOR]