Cornelia de Lange syndrome (CdLS) is a rare multisystem disorder with specific dysmorphic features. Pathogenic genetic variants encoding cohesion complex subunits and interacting proteins (e.g., NIPBL, SMC1A, SMC3, HDAC8, and RAD21) are the major cause of CdLS. However, there are many clinically diagnosed cases of CdLS without pathogenic variants in these genes. To identify further genetic causes of CdLS, we performed whole exome sequencing in 57 CdLS families, systematically evaluating both single nucleotides variants (SNVs) and copy number variations (CNVs). We identified pathogenic genetic changes in 36 out of 57 (63.2 %) families, including 32 SNVs and four CNVs. Two known CdLS genes, NIPBL and SMC1A, were mutated in 23 and two cases, respectively. Among the remaining 32 individuals, four genes (ANKRD11, EP300, KMT2A, and SETD5) each harbored a pathogenic variant in a single individual. These variants are known to be involved in CdLS-like. Furthermore, pathogenic CNVs were detected in NIPBL, MED13L, and EHMT1, along with pathogenic SNVs in ZMYND11, MED13L, and PHIP. These three latter genes were involved in diseases other than CdLS and CdLS-like. Systematic clinical evaluation of all patients using a recently proposed clinical scoring system showed that ZMYND11, MED13L, and PHIP abnormality may cause CdLS or CdLS-like.

Apoptosis is induced by many kinds of therapy-related inducers, such as hyperthermia and chemotherapeutic agents. However, differences in apoptotic pathways between these inducers remain unclear, although knowing the differences is important to map out a therapeutic strategy. Therefore, we focused on the localization and phosphorylation of Bcl-2 and Bax, key mediators of the apoptotic pathway, after hyperthermia and paclitaxel treatment of PC-10 squamous cell carcinoma cells that excessively expressed Bcl-2 and Bax in the cytoplasm. Paclitaxel treatment markedly induced qualitative changes in Bcl-2, whereas hyperthermia did only quantitative changes in Bax. The levels of Bax increased gradually with the duration of hyperthermia, whereas Bcl-2 levels slightly decreased. On the other hand, paclitaxel treatment induced dose-and time-dependent phosphorylation of Bcl-2. Interestingly, phosphorylated Bcl-2 was observed in the specific subcellular sites, mitochondria-and lysosomerich fractions. Both treatments disturbed the heterodimerization of Bax with Bcl-2. Hyperthermia, but not paclitaxel treatment, induced a gradual Bax translocation from the cytoplasm to the nucleus. Although both treatments induced a prominent cell cycle disturbance in the G2M phase, paclitaxel treatment induced typical apoptosis, and hyperthermia hardly induced apoptosis. Our results suggest that the subcellular redistribution of Bax and the phosphorylation of Bcl-2 depend on the type of apoptosis inducers, such as hyperthermia and paclitaxel, and Bcl-2 has a central role in the decision of apoptotic outcome. Our data may afford new insights in apoptosis from the aspect of an association of Bcl-2 phosphorylation with intracellular Bax localization. © 2002 Wiley-Liss, Inc. Key words: Bcl-2; Bax; hyperthermia; paclitaxel; lung cancer cellsPaclitaxel, microtubule-stabilizing agents, demonstrates a marked activity against several kinds of tumors 1 by arresting cell-cycle progression and inducing apoptosis. 2-4 Mild hyperthermia disturbs functions of the microtubule system and triggers apoptosis as well. 5 In addition, local or systemical hyperthermia is used in conjunction with paclitaxel in cancer tretment, 6 but whether a combined thermo-chemotherapy enhanced 5,7,8 or inhibited 9,10 the susceptibility of cells to apoptotic stimuli is still controversial. Therefore, understanding how paclitaxel and hyperthermia modalities induce apoptosis is critical to map out a better anticancer strategy that may offer synergistic benefits when used concurrently.Cellular apoptotic potential is mainly regulated by the relative levels of Bcl-2 and Bax, Bcl-2 family members with opposite functions and their interactions. 11 These proteins mainly act on mitochondria at a critical decision point to irreversible cellular damage. 12-15 The antiapoptotic Bcl-2 suppresses apoptosis, whereas the proapoptotic Bax counteracts the Bcl-2 function to accelerate apoptosis. These proteins exert their activity via protein/ protein interactions, such as homodimerization and heter...

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