ABSTRACT
The International Registry of Werner syndrome (www.wernersyndrome.org) has been providing molecular diagnosis of the Werner syndrome (WS) for the past decade. The present communication summarizes, from among 99 WS subjects, the spectrum of 50 distinct mutations discovered by our group and by others since the WRN gene (also called RECQL2 or REQ3) was first cloned in 1996; 25 of these have not previously been published. All WRN mutations reported thus far have resulted in the elimination of the nuclear localization signal at the C-terminus of the protein, precluding functional interactions in the nucleus; thus, all could be classified as null mutations. We now report two new mutations in the N-terminus that result in instability of the WRN protein. Clinical data confirm that the most penetrant phenotype is bilateral ocular cataracts. Other cardinal signs were seen in more than 95% of the cases. The median age of death, previously reported to be in the range of 46-48 years, is 54 years. Lymphoblastoid cell lines (LCLs) have been cryopreserved from the majority of our index cases, including material from nuclear pedigrees. These, as well as inducible and complemented hTERT (catalytic subunit of human telomerase) immortalized skin fibroblast cell lines are available to qualified investigators.
Subject(s)
DNA Helicases/genetics , Werner Syndrome/diagnosis , Werner Syndrome/genetics , Adult , Aged , Aged, 80 and over , Amino Acid Sequence , DNA Helicases/chemistry , DNA Mutational Analysis , Exodeoxyribonucleases , Humans , Middle Aged , Models, Molecular , Molecular Sequence Data , Pedigree , RecQ Helicases , Registries , Sequence Alignment , Werner Syndrome/mortality , Werner Syndrome HelicaseABSTRACT
The lateral surface of the frontal lobe shows functional activation in a large number of language related tasks. Group analyses, however, demonstrate remarkable intersubject variability of activation. There are different sources for functional variability, anatomical variability being considered as one of them. The aim of the present study therefore was to qualitatively and quantitatively investigate the anatomical variability of the lateral frontal lobe surface and to search for reliable and stable landmarks connected to language functions. MRIs of 23 healthy right-handed subjects were investigated using the publicly available software "Anatomist/BrainVISA". After standardization of the brains (SPM) and sulci identification, the most frequent pattern was determined and the variance of selected landmarks calculated. The variability of the lateral frontal lobe surface is remarkable, particularly in the prefrontal region. Relatively stable landmarks were selected as follows: (1) connection between the superior frontal sulcus (SFS) and the superior precentral sulcus (SPCS); (2) connection between the inferior frontal sulcus (IFS) and the inferior precentral sulcus (IPCS); (3) inferior end of the precentral sulcus (PCS); and (4) origin of the ascending ramus (AscR) of the Sylvian fissure (SYF). The variability (standard deviation) of the spatial coordinates along the 3 axis of these landmarks after normalization ranged from 2.5 to 5.7 mm. The present study demonstrates that intersubject variability of selected landmarks of the frontal lobe surface remains notable even after spatial normalization of the brains. These results support the concept that anatomical variability is a relevant source of functional variability. We therefore suggest to express functional activation in relation to landmarks obtained from individual anatomy. This approach may contribute to a better analysis of the differences between individuals.
