Theresa Larriba Harboe

Molecular cytogenetic characterization of ring chromosome 15 in three unrelated patients

We report molecular cytogenetic characterization of ring chromosome 15 in three unrelated male patients with the karyotype 46,XY,r(15). One was a stillborn child with several malformations, and the other two cases showed pre‐ and postnatal growth retardation and developmental delay, common features for ring chromosome 15 syndrome. One of these patients also displayed clinical features resembling Prader–Willi syndrome (PWS). To delineate the extent of the deletion on chromosome 15, we have carried out fluorescence in situ hybridization (FISH) using bacterial artificial chromosomes (BACs) mapping to the distal long arm of chromosome 15. The deletion breakpoints clustered within a 4.5–6.5 Mb region proximal to the 15q telomere. Two deletions involved the same known genes, while the largest deletion observed in the stillborn child involved three additional genes, including the COUP‐TFII gene, which has been suggested to play a role in heart development. The heart malformations, which are observed in this patient, are thus likely to be due to hemizygosity/haploinsufficiency of the COUP‐TFII gene. In all three patients, the insulin‐like growth factor I receptor gene (IGF1R) gene was deleted supporting the association between IGF1R and growth retardation seen in ring chromosome 15 syndrome.

Human FATE is a novel X-linked gene expressed in fetal and adult testis

Previously, we identified a partial cDNA sequence of a novel human transcript, designated fetal and adult testis expressed transcript (FATE). FATE is testis-specific in fetal life and co-expressed with SRY in a 7 weeks old fetal testis, suggesting a function in early testicular differentiation. Herein, full-length cDNA clones of human and porcine FATE were isolated and the gene structure and promoter region of the human FATE gene was characterized. The human FATE gene, which maps to Xq28, consists of five exons spanning approximately 7 kb of genomic DNA. Examination of 1 kb of the FATE promoter region revealed the presence of a putative steroidogenic factor 1 (SF-1) binding site at position -79 to -71 upstream of the transcription start site. We propose that FATE might represent a novel target gene of SF-1 in human testicular differentiation and/or germ cell development.

A high frequent BRCA1 founder mutation identified in the Greenlandic population

Approximately 10% of all breast and ovarian cancers are dominantly inherited and mutations are mainly found in the BRCA 1 and 2 genes. The penetrance of BRCA1 mutations is reported to be between 68 and 92% and confers a 36–92% life time risk of breast cancer. Most mutations in BRCA1 are uniquely occurring mutations, but founder mutations have been described. In this study we describe a founder mutation with wide spread presence in the Inuit population. We have screened 2,869 persons from Greenland for the presence of a BRCA1 mutation (p.Cys39Gly) only found in the Inuit population. The overall carrier frequency was 1.6% in the general population, but the frequency differs geographically from 0.6% on the West coast to 9.7% in the previously isolated population of the East coast. This is to our knowledge the highest population frequency of a BRCA1 mutation ever to be described. To determine the clinical relevance of the mutation, we have examined ten breast cancer patients and nine ovarian cancer patients from Greenland for the presence of the p.Cys39Gly mutation. We found three ovarian cancer patients (33%) and one breast cancer patient (10%) carrying the mutation. The high number of women carrying a BRCA1 mutation known to trigger the development of potentially lethal diseases leads us to recommend an offer of genetic counselling and test for the mutation to all females of Inuit origin, thereby hopefully preventing a number of breast and ovarian cancer deaths.

Mosaicism in Segmental Darier Disease: An In-Depth Molecular Analysis Quantifying Proportions of Mutated Alleles in Various Tissues

Darier disease is an autosomal dominant genodermatosis caused by germline mutations in the ATP2A2 gene. Clinical expression is variable, including rare segmental phenotypes thought to be caused by postzygotic mosaicism. Genetic counseling of segmental Darier patients is complex, as risk of transmitting a nonsegmental phenotype to offspring is of unknown magnitude. We present the first in-depth molecular analysis of a mosaic patient with segmental disease, quantifying proportions of mutated and normal alleles in various tissues. Pyrosequence analysis of DNA from semen, affected and normal skin, peripheral leukocytes and hair revealed an uneven distribution of the mutated allele, from 14% in semen to 37% in affected skin. We suggest a model for segmental manifestation expression where a threshold number of mutated cells is needed for manifestation development. We further recommend molecular analysis of the ATP2A2 gene in semen of male patients with segmental Darier disease to improve genetic counseling.

Assignment1 of the human zinc finger gene, ZNF288, to chromosome 3 band q13.2 by radiation hybrid mapping and fluorescence in situ hybridisation

Zinc finger genes comprise a large family of genes, which have been associated with normal and abnormal development, including development of extremities, regulation of neuronal gene expression (Theil et al., 1999), motor neuron development and migration (Baum et al., 1999), and abnormal brain development (Karlstrom et al., 1999). Zinc finger genes have also been associated with cancer (Stein et al., 1999) and systemic lupus erythematosus (Tsao et al., 1999). The human zinc finger gene, ZNF288, has high homology to a novel murine POZ/zinc finger transcription factor encoding gene, Oda-8, which is expressed in developing neurons during mouse brain development (Kjaerulf et al., unpublished, accession number AL050276). Although the function of ZNF288 remains to be elucidated, it is tempting to speculate that ZNF288 codes for a protein that may be involved in brain development. Here we report the assignment of the human ZNF288 gene to human chromosome 3q13.2 by radiation hybrid mapping and fluorescence in situ hybridisation (FISH). Materials and methods

ILDS Newsletter No. 19

After having returned from an outstanding and stimulating world congress in Seoul, it is my pleasure to invite you to read the fi rst ILDS newsletter edited by the newly elected Board. The ILDS Board and I as its President will do our best to stay in touch with you, and to jointly work on many important issues to be tackled and solved during the forthcoming four years. Please see a photo of the new Board as well as a list of all Board members as well as their email addresses below. Please contact me as your President directly, or contact the league through Regional Board members, or simply those who you know best. The new Board of the ILDS has started its work for the ongoing term, and we are aiming to identify the areas that deserve most of our attention. To prepare the ground, the Board will hold a full day strategy retreat in October 2011, prior to the EADV meeting in Lisbon. We will have several committees within the ILDS Board, and the chairpersons will report in one of the forthcoming newsletters on their work in detail. Thus, you can follow and comment our activities. It is the predominant task of the ILDS to organize the World Congress of Dermatology every four years, and therefore the preparations for the next WCD have to be initiated right away. The Program Committee is already assigned and will, under the leadership of Prof Jean Bolognia, work hard to ensure a successful program. However, some framework discussions need to take place at the retreat meeting before we can go ahead. Questions pertinent to the WCD include: what are the unique strengths of a WCD, how can we improve further its attractiveness, should other professions – i.e. dermatological nurses – be involved as well, how can we best balance between the diff erent subspecialties of dermatology, and what is the ideal length of a WCD? Some of you have already come up with suggestions, and we ask you to contact us for criticisms or proposals. As you may know, there many other issues in which the ILDS is involved. In fact, the ILDS entertains strong philanthropic activities, such as the Regional Dermatology Training Center in Moshi, Tanzania. Here, in the Kilimanjaro region, many African dermatologists are trained, and we can be proud of our successful work, which – by the way – is supported by many of our member societies, either independently or via the International Foundation of Dermatology, a subcommittee of the ILDS. As it is often the case, such successful activities are seen by others, who then are keen to support and to help further. In one of the forthcoming issues of the ILDS newsletter, we will report on a new project in the context of the Moshi training center, called Hats on for Skin Health. I am sure you will be surprised and pleased. The ILDS is the league of dermatological societies around the globe, and we believe it is important that the leaders of these societies engage more frequently. Therefore, the ILDS will host receptions for the Presidents and selected offi cers of our member societies, in order to exchange thoughts, concerns and new concepts on a global scale. We will regularly hold such receptions at the annual meetings of AAD and EADV, with other possible locations. Next year, we will organize an ILDS Dermatology Summit, which will take place from June 4–5, in Berlin. Presidents and other representatives of all member societies are being invited to discuss opportunities and challenges in dermatology on a global scale. From these discussions, we hope to initiate programs and activities that will strengthen and further develop our discipline. At our retreat meeting in October this year, we will discuss a draft agenda which will be distributed to all member societies for further input. The scope of dermatology diff ers geographically, and we need to fi nd ways to strengthen areas of our discipline that are not represented globally, but which are of utmost importance where they belong to dermatology. Such fi elds include, among others, venereology (which belongs to dermatology is many parts of the world), allergy, dermatopathology, proctology, leprology, mycology, and even andrology. We will defi nitively involve you, and learn from you, on our way towards a successful future. Personally, I strongly believe that the ILDS, the International League of Dermatological Societies, is the organization to identify and to tackle the problems we are facing in dermatology, and to develop strategies to identify and overcome them. Without any doubt, the ILDS represents an enormous source of knowledge and experience and, together, we will be strong enough to bring dermatology and its subspecialities into an excellent and rewarding position, thus maintaining and improving the care for our patients. Please help us, invest time and support our projects.

Assignment of Zfp100 to murine chromosome 4 band D3/E1 with radiation hybrid mapping.

Zinc finger genes have been shown to be involved in many different functions of the organism, such as development, differentiation (Krempler et al., 1999) and cancer (Stein et al., 1999). The human zinc finger gene ZNF151, has high homology to a murine POZ/zinc finger transcription factor gene, Zfp100, which is expressed in most tissues. Peukert et al. (1997) found that ZNF151 has a potent growth reducing effect on HeLa cells. Although the function of Zfp100 remains to be elucidated, it is tempting to speculate that Zfp100 codes for a protein that may play an important role in development. Here we report the assignment of the murine Zfp100 gene to chromosome 4 by radiation hybrid mapping