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Lines M.A.,University of Ottawa | Huang L.,University of Ottawa | Schwartzentruber J.,McGill University | Douglas S.L.,University of Ottawa | And 22 more authors.
American Journal of Human Genetics | Year: 2012

Mandibulofacial dysostosis with microcephaly (MFDM) is a rare sporadic syndrome comprising craniofacial malformations, microcephaly, developmental delay, and a recognizable dysmorphic appearance. Major sequelae, including choanal atresia, sensorineural hearing loss, and cleft palate, each occur in a significant proportion of affected individuals. We present detailed clinical findings in 12 unrelated individuals with MFDM; these 12 individuals compose the largest reported cohort to date. To define the etiology of MFDM, we employed whole-exome sequencing of four unrelated affected individuals and identified heterozygous mutations or deletions of EFTUD2 in all four. Validation studies of eight additional individuals with MFDM demonstrated causative EFTUD2 mutations in all affected individuals tested. A range of EFTUD2-mutation types, including null alleles and frameshifts, is seen in MFDM, consistent with haploinsufficiency; segregation is de novo in all cases assessed to date. U5-116kD, the protein encoded by EFTUD2, is a highly conserved spliceosomal GTPase with a central regulatory role in catalytic splicing and post-splicing-complex disassembly. MFDM is the first multiple-malformation syndrome attributed to a defect of the major spliceosome. Our findings significantly extend the range of reported spliceosomal phenotypes in humans and pave the way for further investigation in related conditions such as Treacher Collins syndrome. © 2012 The American Society of Human Genetics.


Kiritsi D.,Albert Ludwigs University of Freiburg | Kern J.S.,Albert Ludwigs University of Freiburg | Schumann H.,Albert Ludwigs University of Freiburg | Kohlhase J.,Center for Human Genetics Freiburg | And 2 more authors.
Journal of Medical Genetics | Year: 2011

Background: Junctional epidermolysis bullosa (JEB), a group of hereditary skin fragility disorders, is associated with a wide variety of phenotypes, although all forms are characterised by trauma induced skin blistering and tissue separation at the dermaleepidermal junction zone. A subgroup, coined JEB-other, is associated with mutations in the COL17A1 gene encoding collagen XVII or, more rarely, with mutations in the laminin 332 genes LAMA3, LAMB3, or LAMC2. The objective of this study is comprehensive genotypeephenotype analysis in JEB-other patients with COL17A1 mutations and elucidation of disease mechanisms underlying different skin phenotypes. Methods and results: COL17A1 mutations and their clinical and cellular consequences were systematically analysed in 43 patients with JEB-other. Cell culture, RT-PCR, and protein biochemistry were applied to assess the effects of splice site mutationsdthat is, the nature and amounts of transcripts and polypeptides synthesised and their association with the phenotypic outcome. 34 distinct COL17A1 mutations were disclosed, 12 of them novel. mRNA and protein analyses demonstrated that patients with only about 12-14% of the physiological collagen XVII levels had mild cutaneous involvement and a long life span. Conclusions: In contrast to complete null phenotypes, presence of minor amounts of collagen XVII protein in JEB skin is associated with mild phenotypic manifestations. The data have significant implications for design of molecular therapies for JEB, since they suggest that already a low extent of collagen XVII restoration will improve skin stability and alleviate symptoms.


Pigors M.,Albert Ludwigs University of Freiburg | Kiritsi D.,Albert Ludwigs University of Freiburg | Krumpelmann S.,Princess Margaret Childrens Hospital | Wagner N.,Clinic Darmstadt GmbH | And 6 more authors.
Human Molecular Genetics | Year: 2011

Epidermal integrity is essential for skin functions. It is maintained by adhesive structures between keratinocytes, mainly the desmosomes and adherens junctions, which provide resistance against mechanical stress and regulate the formation of the skin barrier. As a constituent of both types of intercellular junctions, plakoglobin has multiple interaction partners and mutations in its gene [junction plakoglobin (JUP)] have been associated with mild cutaneous disease, palmoplantar keratoderma and arrhythmogenic heart disease. Here we report a novel lethal phenotype caused by a homozygous nonsense JUP mutation, c.1615C>T, p.Q539X, which is very different from any human or murine JUP phenotype described so far. The patient suffered from severe congenital skin fragility with generalized epidermolysis and massive transcutaneous fluid loss, but apparently no cardiac dysfunction. In contrast to previously reported JUP mutations where truncated proteins were still present, in this case there was complete loss of plakoglobin in the patient's skin, as demonstrated by immunofluorescence and immunoblot analysis. As a consequence, only very few abnormal desmosomes were formed and no adhesion structures between keratinocytes were recognizable. The expression and distribution of desmosomal components was severely affected, suggesting an essential role for plakoglobin in desmosomal assembly. Adherens junction proteins were localized to keratinocyte plasma membrane, but did not provide proper cell-cell adhesion. This lethal congenital epidermolysis bullosa highlights the fundamental role of plakoglobin in epidermal cohesion. © The Author 2011. Published by Oxford University Press. All rights reserved.


Has C.,Albert Ludwigs University of Freiburg | Castiglia D.,Instituto Dermopatico dellImmacolata IRCCS | del Rio M.,CIEMAT | Garcia Diez M.,CIEMAT | And 8 more authors.
Human Mutation | Year: 2011

Mutations in the FERMT1 gene (also known as KIND1), encoding the focal adhesion protein kindlin-1, underlie the Kindler syndrome (KS), an autosomal recessive skin disorder with an intriguing progressive phenotype comprising skin blistering, photosensitivity, progressive poikiloderma with extensive skin atrophy, and propensity to skin cancer. Herein we review the clinical and genetic data of 62 patients, and delineate the natural history of the disorder, for example, age at onset of symptoms, or risk of malignancy. Although most mutations are predicted to lead to premature termination of translation, and to loss of kindlin-1 function, significant clinical variability is observed among patients. There is an association of FERMT1 missense and in-frame deletion mutations with milder disease phenotypes, and later onset of complications. Nevertheless, the clinical variability is not fully explained by genotype-phenotype correlations. Environmental factors and yet unidentified modifiers may play a role. Better understanding of the molecular pathogenesis of KS should enable the development of prevention strategies for disease complications. ©2011 Wiley Periodicals, Inc.


Arnold A.W.,University of Basel | Itin P.H.,University of Basel | Pigors M.,Albert Ludwigs University of Freiburg | Kohlhase J.,Center for Human Genetics Freiburg | And 2 more authors.
British Journal of Dermatology | Year: 2010

A new syndrome with poikiloderma was described by Clericuzio et al. in 1991.1 They reported 14 Navajo native Americans, including eight siblings, developing in the first year of life an erythematous rash, which started on the limbs and spread over the trunk and the face. This rash evolved into poikiloderma. All patients had recurrent bacterial infections. First published as Navajo poikiloderma this syndrome is now known as poikiloderma with neutropenia (PN, OMIM 604173). The inheritance is autosomal recessive, and mutations in a new gene, C16orf57, were recently described in two kindreds. 2 Because of the phenotypic overlap between Rothmund-Thomson syndrome (RTS) and PN, a few patients have been reclassified as mutations in the RECQL4 gene for RTS were absent.2-5 Until now 27 patients have been described with clinical PN.1-3,5-8 Here, we report the sixth family with PN outside the Navajo population. We found the previously unreported mutation c.243G>A, p.W81X in the C16orf57 gene, thus confirming the relation of this gene to the disease.2,6 Because the molecular genetic diagnosis is not always available, we propose clinical and laboratory diagnostic criteria for PN. © 2010 British Association of Dermatologists.


Schumann H.,Albert Ludwigs University of Freiburg | Schumann H.,Catholic University of Applied Sciences at Freiburg | Kiritsi D.,Albert Ludwigs University of Freiburg | Pigors M.,Albert Ludwigs University of Freiburg | And 10 more authors.
British Journal of Dermatology | Year: 2013

Background Integrin α6β4 is a transmembrane receptor and a key component of the hemidesmosome anchoring complex. It is involved in cell-matrix adhesion and signalling in various tissues. Mutations in the ITGA6 and ITGB4 genes coding for α6β4 integrin compromise dermal-epidermal adhesion and are associated with skin blistering and pyloric atresia (PA), a disorder known as epidermolysis bullosa with PA (EB-PA). Objectives To elucidate the molecular pathology of skin fragility in eight cases, disclose the underlying ITGA6 and ITGB4 mutations and study genotype-phenotype correlations. Methods DNA was isolated from ethylenediaminetetraacetic acid-blood samples, and the coding exons and exon-intron boundaries of ITGA6 and ITGB4 were amplified by polymerase chain reaction (PCR), and directly sequenced. Skin samples were submitted to immunofluorescence mapping with antibodies to adhesion proteins of the dermal-epidermal junction. Primary keratinocytes were isolated, and used for RNA and protein extraction, reverse transcription PCR and immunoblotting. Ultrastructural analysis of the skin was performed in one patient. Results We disclose 10 novel mutations, one in ITGA6 and nine in ITGB4. Skin cleavage was either intraepidermal or junctional. Lethal outcome and PA correlated with loss-of-function mutations in two cases. Solely mild skin involvement was associated with deletion of the C-terminus of β4 integrin. Combinations of missense, nonsense or frameshift mutations caused severe urinary tract involvement in addition to skin fragility in five cases. Conclusions The present study reveals novel ITGA6 and ITGB4 gene mutations and supports previous reports showing that the phenotype may lack PA and be limited to skin and nail involvement. In four out of six cases of EB-PA, life expectancy was not impaired. A high frequency of urinary tract involvement was found in this study, and represented the main cause of morbidity. Low levels of β4 integrin expression were compatible with hemidesmosomal integrity and a mild skin phenotype. What's already known about this topic? Epidermolysis bullosa (EB) with pyloric atresia (PA) is a rare EB type caused by mutations in the genes coding for α6β4 integrin or plectin, disrupting the hemidesmosome adhesion complex. A reduced life expectancy is predicted in most cases of EB with PA. α6β4 integrin gene mutations are not always associated with PA. What does this study add? This study identifies 10 novel ITGB4 and ITGA6 mutations causing a spectrum of phenotypes, ranging from mild skin blistering to a lethal multisystem disorder with skin, urinary and gastrointestinal involvement. Urinary tract involvement is relatively common (five out of eight cases in this study). Low levels of α6β4 integrin are sufficient for hemidesmosomal integrity and are associated with a mild skin phenotype. © 2013 The Authors BJD © 2013 British Association of Dermatologists.


Has C.,Albert Ludwigs University of Freiburg | Burger B.,University of Basel | Volz A.,Albert Ludwigs University of Freiburg | Kohlhase J.,Center for Human Genetics Freiburg | And 2 more authors.
Dermatology | Year: 2010

Kindler syndrome (KS) is a heritable skin disorder with a complex phenotype consisting of congenital skin blistering, photosensitivity, progressive generalized poikiloderma and extensive skin atrophy. Here we describe 2 siblings with KS, who are, to the best of our knowledge, the oldest patients reported so far in the literature. The diagnosis was established in their seventh and eighth decades of life, and confirmed by mutation analysis. Both patients were homozygous for the recurrent FERMT1 mutation, c.328C→T, p.R110X. Because of a relatively mild course of the disease, mucosal membranes in the eyes and oesophagus being predominantly affected in recent years, they had been treated under other diagnoses, such as scleroderma. Cutaneous precancerous lesions and epithelial skin cancer arose in both siblings after the age of 50 years and were treated in an early stage. Taken together, we describe the natural course of KS, the morphological abnormalities occurring in the skin of older KS patients, we discuss the differential diagnosis and the association between KS and squamous cell carcinoma. Copyright © 2010 S. Karger AG, Basel.


PubMed | Medical Doctor, Regional Hospital, Center for Human Genetics Freiburg, University of Strasbourg and University Paris Diderot
Type: Journal Article | Journal: American journal of medical genetics. Part A | Year: 2016

Mandibuloacral dysplasia with type B lipodystrophy is a rare autosomal recessive disease characterized by atrophic skin, lipodystrophy, and skeletal features. It is caused by mutations in ZMPSTE24, a gene encoding a zinc metalloproteinase involved in the post-translational modification of lamin. Nine distinct pathogenic variants have been identified in 11 patients from nine unrelated families with this disorder. We report a 12-year-old boy with mandibuloacral dysplasia with type B lipodystrophy and a novel homozygous c.1196A>G; p.(Tyr399Cys) mutation in ZMPSTE24. The patient had typical dermatological and skeletal features of mandibuloacral dysplasia with type B lipodystrophy, sparse hair, short stature, mild microcephaly, facial dysmorphism, and a striking failure of ossification of the interparietal region of the occipital bone, up to the position where transverse occipital suture can be observed. Newly recognized signs for mandibuloacral dysplasia with type B lipodystrophy were gaze palsy and ptosis. Delayed closure of cranial sutures and Wormian bones have been described in three patients, but an ossification failure strictly limited to the occipital bone, as seen in the present patient, appears to be unique for mandibuloacral dysplasia with type B lipodystrophy. This observation illustrates that ZMPSTE24 could play a specific role in membranous ossification in the interparietal part of the squama (Inca bone) but not in the intracartilaginous ossification of the supraoccipital. This failure of ossification in the squama appears to be a useful feature for the radiological diagnosis of mandibuloacral dysplasia with type B lipodystrophy. 2016 Wiley Periodicals, Inc.


Mehraein Y.,Ludwig Maximilians University of Munich | Schmid I.,Ludwig Maximilians University of Munich | Eggert M.,Ludwig Maximilians University of Munich | Kohlhase J.,Center for Human Genetics Freiburg | Steinlein O.K.,Ludwig Maximilians University of Munich
Cancer Letters | Year: 2016

DICER1, a RNAse endonuclease involved in the processing of siRNA and microRNA, is known to play a pivotal role in the post-transcriptional regulation of gene expression. Germ line mutations in the DICER1 gene increase the risk for different types of tumors. At present, DICER1 syndrome is an established, though not well defined, member of the group of genetic tumor predisposition syndromes. Here, we report a DICER1 syndrome family with a medical history of different rare tumors mostly occurring at a young age. The tumor spectrum in this family included both DICER1 syndrome-typical forms, such as pleuropulmonary blastoma, multinodular goiter, and cystic nephroma, and not previously reported manifestations, such as pilomatrixoma, and juvenile basal cell carcinoma. The latter tumor types are usually considered to be indicators of familial adenomatous polyposis and basal cell nevus syndrome. © 2015 Elsevier Ireland Ltd.


PubMed | Ludwig Maximilians University of Munich and Center for Human Genetics Freiburg
Type: Journal Article | Journal: Cancer letters | Year: 2015

DICER1, a RNAse endonuclease involved in the processing of siRNA and microRNA, is known to play a pivotal role in the post-transcriptional regulation of gene expression. Germ line mutations in the DICER1 gene increase the risk for different types of tumors. At present, DICER1 syndrome is an established, though not well defined, member of the group of genetic tumor predisposition syndromes. Here, we report a DICER1 syndrome family with a medical history of different rare tumors mostly occurring at a young age. The tumor spectrum in this family included both DICER1 syndrome-typical forms, such as pleuropulmonary blastoma, multinodular goiter, and cystic nephroma, and not previously reported manifestations, such as pilomatrixoma, and juvenile basal cell carcinoma. The latter tumor types are usually considered to be indicators of familial adenomatous polyposis and basal cell nevus syndrome.

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