Hypotrichosis simplex (HS) with and without woolly hair (WH) comprises a group of rare, monogenic disorders of hair loss. Patients present with a diffuse loss of scalp and/or body hair, which usually begins in early childhood and progresses into adulthood. Some of the patients also show hair that is tightly curled. Approximately 10 genes for autosomal recessive and autosomal dominant forms of HS have been identified in the last decade, among them five genes for the dominant form. We collected blood and buccal samples from 17 individuals of a large British family with HS and WH. After having sequenced all known dominant genes for HS in this family without the identification of any disease causing mutation, we performed a genome-wide scan, using the HumanLinkage-24 BeadChip, followed by a classical linkage analysis; and whole exome-sequencing (WES). Evidence for linkage was found for a region on chromosome 4q35.1-q35.2 with a maximum LOD score of 3.61. WES led to the identification of a mutation in the gene SORBS2, encoding sorbin and SH3 domain containing 2. Unfortunately, we could not find an additional mutation in any other patient/family with HS; and in cell culture, we could not observe any difference between cloned wildtype and mutant SORBS2 using western blotting and immunofluorescence analyses. Therefore, at present, SORBS2 cannot be considered a definite disease gene for this phenotype. However, the locus on chromosome 4q is a robust and novel finding for hypotrichosis with woolly hair. Further fine mapping and sequencing efforts are therefore warranted in order to confirm SORBS2 as a plausible HS disease gene.
The neuronal ceroid-lipofuscinosis (NCL) are a heterogeneous group of neurodegenerative diseases charac- terized by the lysosomal accumulation of ceroid and lip- ofuscin with mitochondrial ATP synthase subunit C in various tissues. Clinical features include progressive mental and motor deterioration, myoclonus, seizure, visual failure and premature death. Ten CLN genes have been identified, among them CLN6 genes for which 55 disease-causing mutations have already been reported. The authors describe here a large consanguineous Moroccan family with three affected patients due to the p.I154del mutation that has been exclusively reported in Portuguese patients. This is the first published report of a genetic study in a Moroccan family with NCL. A relatively inexpensive CLN6 mutation screen- ing should be considered first in Morocco as an initial diagnosis step when the disease course is consistent with late infantile neuronal ceroid-lipofuscinosis.
Abstract Alopecia areata is an immune‐mediated disorder, occurring with the highest observed frequency in the rare recessive autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) syndrome caused by mutations of the autoimmune regulator ( AIRE ) gene on chromosome 21q22.3. We have previously detected association between alopecia areata and a single nucleotide polymorphism (SNP) in the AIRE gene in patients without APECED, and we now report the findings of an extended examination of the association of alopecia areata with haplotype analysis including six SNPs in the AIRE gene: C‐103T, C4144G, T5238C, G6528A, T7215C and T11787C. In Caucasian groups of 295 patients and 363 controls, we found strong association between the AIRE 7215C allele and AA [ P = 3.8 × 10 −8 , OR (95% CI): 2.69 (1.8–4.0)]. The previously reported association between AA and the AIRE 4144G allele was no longer significant on correction for multiple testing. The AIRE haplotypes CCTGCT and CGTGCC showed a highly significant association with AA [ P = 6.05 × 10 −6 , 9.47 (2.91–30.8) and P = 0.001, 3.51 (1.55–7.95), respectively]. To select the haplotypes most informative for analysis, we tagged the polymorphisms using SNPTag software. Employing AIRE C‐103T, G6528A, T7215C and T11787C as tag SNPs, two haplotypes were associated with AA; AIRE CGCT and AIRE CGCC [ P = 3.84 × 10 −7 , 11.40 (3.53–36.9) and P = 3.94 × 10 −4 , 2.13 (1.39–3.24) respectively]. The AIRE risk haplotypes identified in this study potentially account for a major component of the genetic risk of developing alopecia areata.
Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease. Ten of fifteen causative genes linked to familial forms of PD have been reported to cause autosomal recessive forms. Among them, mutations in the PTEN-induced kinase 1 ( PINK1 ) gene were shown to be responsible for a phenotype characterized by early onset, good response to levodopa, and a benign course. Using chromosomal microarray analysis and Sanger sequencing, we identified a homozygous G/C substitution in a 58-year-old Moroccan man diagnosed with recessive inherited Parkinson’s disease. This G-to-C transition occurred at position 1617 leading to an amino acid change L/F at position 539 located in highly conserved motif in the C terminal sequence of PINK1 . Interestingly, the c.1617G>C substitution is absent in 192 ethnically matched control chromosomes. Our findings have shown that the p.L539F is a novel mutation located in the C terminal sequence of the PINK1 protein that could be pathogenic and responsible for a clinical phenotype resembling idiopathic Parkinson’s disease with rapid progression and early cognitive impairment.
Zusammenfassung: Die Häufigkeit der Alopecia areata und die beobachteten Vererbungsmuster sind mit einem polygenen Vererbungsmodell in Einklang zu bringen, doch ist die Genetik der Alopecia areata bis heute letztlich größtenteils unbekannt. Spekulativ bleibt auch die Bedeutung von Umgebungsfaktoren, die Erkrankungsbeginn oder Exazerbation triggern können. Nimmt man den Zugang über das Kandidatengen, so konnten drei Susceptibilitäts‐/Härtefaktoren identifiziert werden. Zunächst zeigten HLA‐Allele eine starke Assoziation mit Alopecia areata und einige DQB‐ und DR‐Allele bringen sowohl in Fall‐Kontroll‐Studien als auch in Familienstudien ebenfalls ein höheres Erkrankungsrisiko mit sich. Interleukin‐1 Clustergene, hauptsächlich die Interleukin‐1‐Rezeptor‐Antagonisten, sind mit der Erkrankungsschwere der Alopecia areata und einer Reihe anderer Autoimmun‐ und entzündlicher Erkrankungen deutlich assoziiert. Schließlich sind auch die Assoziation der Alopecia areata mit dem Down‐Syndrom, die größere Häufigkeit der Alopecia areata beim autoimmunen polyglandulären Syndrom Typ I aufgrund von Mutationen des autoimmunen Regulatorgens (AIRE) auf Chromosom 21q22.3, und der Nachweis der Assoziation mit MX1, einem anderen Gen in der Region des Down‐Syndroms auf Chromosom 21, Hinweise dafür, dass dieser Bereich des Genoms ein vielversprechendes Ziel für zukünftige Familienuntersuchungen darstellt. Die Bedeutung einzelner Gene des MHC, des IL‐1‐Clusters oder auf Chromosom 21q22.3 ist schwer einzuschätzen und es sind weitere genetische und funktionelle Untersuchungen erforderlich, um ihre Beteiligung an der Pathogenese der Alopecia areata zu bestätigen.
Alopecia areata is characterized by a reversible form of patchy or complete hair loss associated with T-cell infiltration of hair follicles. The lifetime disease risk of approximately 1.4% in the general population is increased to more than 30% in autoimmune polyendocrinopathy candidiasis ectodermal dysplasia syndrome (APECED), a recessive condition resulting from a mutation of the autoimmune regulator (AIRE) gene on chromosome 21q22.3. Aire protein is thought to have transcriptional regulatory activity but its role is not well defined at present. In this study, we have examined the possible involvement of AIRE in the pathogenesis of alopecia areata. On screening the AIRE coding sequence, we identified 20 variants. Two of these at positions, G961C and T1029C, give rise to amino acid changes, S278R and V301A, located in the DNA-binding segment (SAND) and PHD1 zinc finger motif, respectively. We found no difference in the frequency of the AIRE T1029C polymorphism between the control and patient groups. We genotyped 202 alopecia areata patients and 175 matched Caucasian controls for the AIRE G961C alleles. The frequency of the rare allele (961G) was 0.08 in the controls and there was a significant increase to 0.13 in alopecia areata overall and 0.20 in severe disease (alopecia universalis). We found no association between the AIRE G961G variant and mild (patchy) alopecia areata or alopecia totalis. However, the AIRE 961G allele is a potent risk factor (> 3) for the severest form of alopecia areata, and for disease of early age at onset (at 30 years). The change from serine to arginine in the SAND domain of AIRE protein may have a significant effect on AIRE DNA-binding activity. Moreover, our results could provide a rational explanation of the unusually high frequency of AA in APECED patients, supporting the concept of AA as an autoimmune disease.
During normal stratification of the epidermis, keratinocytes undergo a complex programme of terminal differentiation. This programmed cell death results in corneocyte accumulation to form the stratum corneum (SC). Terminal differentiation and apoptosis share numerous features such as elimination of nuclei and organelles, changes in cell shape, and activation of transglutaminases and proteases. Caspases are cysteine proteases that play a central role in apoptosis. Therefore they may also be involved in the terminal differentiation of keratinocytes.To identify the caspases expressed in normal human epidermis and to define their pattern of expression and activation.We analysed mRNAs from human epidermis by reverse transcription-polymerase chain reaction (RT-PCR), skin cryosections by immunohistological methods, and epidermal protein extracts by Western blotting.The mRNAs encoding caspase-1, -2, -3, -4, -6, -7, -8, -9, -10 and -14 were detected by RT-PCR. Accordingly, the immunohistological analyses showed clear expression in the epidermis of the corresponding proteins except caspase-2 and caspase-8, with only a weak expression of caspase-9. Moreover, procaspase-1, -2, -3, -4, -6, -7, -9, -10 and -14, and the fully processed caspase-14, were immunodetected in total epidermis extracts. However, only procaspase-1 and the processed caspase-14 were detected in extracts of superficial SC. In addition to these two proteins, procaspase-4 was detected in extracts of superficial SC obtained from lesional psoriatic skin.This study, the first exhaustive description of caspase expression and processing in normal human epidermis, indicates that in vivo granular keratinocytes express nine procaspases, and in addition the activated form of caspase-14. This confirms that only caspase-14 is involved in keratinocyte differentiation, and suggests that keratinocytes are ready to induce apoptosis in response to cutaneous damage.
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