Albinism is a clinically and genetically heterogeneous disease characterized by variable degrees of hypopigmentation and by nystagmus, foveal hypoplasia, and chiasmatic misrouting of the optic nerves. The wide phenotypic heterogeneity impedes the establishment of phenotype-genotype correlations. To obtain a precise diagnosis, we screened the 19 known albinism genes in 990 index patients using targeted next-generation sequencing (NGS) and high-resolution comparative genomic hybridization. A molecular diagnosis was obtained in 72.32% of patients. A total of 243 new pathogenic variants were identified. Intragenic rearrangements represented 10.8% of all pathogenic alleles. NGS panel analysis allowed establishing a diagnosis for the rarest forms of the disease, which could not be diagnosed otherwise. Because of the clinical overlap between the different forms of the disease, diagnosis nowadays clearly relies on molecular grounds.
Purpose.-Hermansky-Pudlak syndrome (HPS) is characterized by oculocutaneous albinism, excessive bleeding, and often additional symptoms. Variants in 10 different genes have been involved in HPS. However, some patients lack variants in these genes. We aimed to identify new genes involved in non-syndromic or syndromic forms of albinism.Methods.-230 albinism patients lacking a molecular diagnosis of albinism were screened for pathogenic variants in candidate genes with known links to pigmentation or HPS pathophysiology.Results.-We identified two unrelated patients with distinct homozygous variants of the BLOC1S5 gene. Patients had mild oculocutaneous albinism, moderate bleeding diathesis, platelet aggregation deficit and a dramatically decreased number of platelet dense granules, all signs compatible with HPS. Functional tests performed on platelets of one patient displayed an absence of the obligate multi-subunit complex BLOC-1, showing that the mutation disrupts BLOC1S5 function and impairs BLOC-1 assembly. Expression of the patient-derived BLOC1S5 deletion in non-pigmented murine Bloc1s5 −/− melan-mu melanocytes failed to rescue pigmentation, the assembly of a functional BLOC-1 complex, and melanosome cargo trafficking, unlike the wildtype allele.Conclusion.-Mutation of BLOC1S5 is disease-causing, and we propose that BLOC1S5 is the gene for a new form of Hermansky-Pudlak syndrome, HPS-11.
Purpose. Albinism is a clinically and genetically heterogeneous condition. Despite analysis of the twenty known genes, ~30% patients remain unsolved. We aimed to identify new genes involved in albinism.Methods. We sequenced a panel of genes with known or predicted involvement in melanogenesis in 230 unsolved albinism patients. Results. We identified variants in theDopachrome tautomerase (DCT) gene in two patients. One was compound heterozygous for a 14 bp deletion in exon 9 and c.118T>A p.(Cys40Ser). The second was homozygous for c.183C>G p.(Cys61Trp). Both patients had mild hair and skin hypopigmentation, and classical ocular features. CRISPR-Cas9 was used in C57BL/6J mice to create mutations identical to the missense mutations carried by the patients, along with one loss-of-function indel mutation. When bred to homozygosity the three mutations revealed hypopigmentation of the coat, milder for Cys40Ser compared to Cys61Trp or the frameshift mutation. Histological analysis identified significant hypopigmentation of the retinal pigmented epithelium (RPE) indicating that defective RPE melanogenesis could be associated with eye and vision defects. DCT loss of function in zebrafish embryos elicited hypopigmentation both in melanocytes and RPE cells. Conclusions. DCT is the gene for a new type of oculocutaneous albinism that we propose to name OCA8.
Genetic diseases have been historically segregated into rare Mendelian disorders and common complex conditions. Large-scale studies using genome sequencing are eroding this distinction and are gradually unmasking the underlying complexity of human traits. Here, we analysed data from the Genomics England 100,000 Genomes Project and from a cohort of 1313 individuals with albinism aiming to gain insights into the genetic architecture of this archetypal rare disorder. We investigated the contribution of protein-coding and regulatory variants both rare and common. We focused on TYR, the gene encoding tyrosinase, and found that a high-frequency promoter variant, TYR c.−301C>T [rs4547091], modulates the penetrance of a prevalent, albinism-associated missense change, TYR c.1205G>A (p.Arg402Gln) [rs1126809]. We also found that homozygosity for a haplotype formed by three common, functionally-relevant variants, TYR c.[−301C;575C>A;1205G>A], is associated with a high probability of receiving an albinism diagnosis (OR>82). This genotype is also associated with reduced visual acuity and with increased central retinal thickness in UK Biobank participants. Finally, we report how the combined analysis of rare and common variants can increase diagnostic yield and can help inform genetic counselling in families with albinism.
To cite this version:Solène Monfermé. A mild form of oculocutaneous albinism type 1: phenotypic analysis of compound heterozygous patients with the R402Q variant of the TYR gene. Human health and pathology. 2017. dumas-01787599 Année 2017 Thèse N° 3074 U.F.R. des Sciences Médicales THÈSE Pour l'obtention du DIPLOME D'ETAT DE DOCTEUR EN MEDECINE Discipline : Ophtalmologie Présentée et soutenue publiquement le 07 juillet 2017 par Solène MONFERMÉ née le 5 aout 1988 à Neuilly-sur-Seine A notre respectée coordinatrice de DES et présidente du jury, Madame le Professeur Marie-Noëlle Delyfer, Je vous suis extrêmement reconnaissante pour votre investissement dans la formation des internes en tant que coordinatrice du DES d'ophtalmologie, veillant sur chacun d'entre nous, disponible et à l'écoute dès notre première année d'internat et aux étapes clef de notre cursus. Votre professionnalisme, votre rigueur, mais aussi, vos qualités humaines et votre bienveillance sont pour moi autant d'exemples que je n'aurai de cesse de tenter d'imiter. Merci de me faire l'honneur de juger ce travail et de présider ce jury. Soyez assurée de ma reconnaissance et de ma sincère admiration. A mon Maître et directeur de Thèse, Monsieur le Docteur Clément Paya,Tu as conforté mon goût pour l'ophtalmo-pédiatrie, à l'écoute dès mon premier semestre au CHU, me fournissant déjà d'excellents conseils pour l'internat en général et pour une orientation en pédiatrie d'autre part. Je te dois cette excellente expérience au sein du service du Dr Caputo à la Fondation Rothschild, que tu m'avais recommandé. Merci de m'avoir suggéré ce travail sur un thème qui m'a passionné et beaucoup enrichie au contact de l'équipe de génétique du CHU de Bordeaux. Merci pour tes conseils toujours très justes pendant la rédaction de ce travail, pour ta rigueur scientifique et ton goût de la recherche que tu m'auras j'espère un peu transmis, pour ta patience et ta grande disponibilité, pour tes encouragements et ta confiance. Merci enfin et surtout pour le modèle de médecin que tu es, consciencieux, passionné, patient et à l'écoute avec tes patients de tous âges. J'espère parvenir à m'en inspirer pour ma pratique future.A mon rapporteur, Monsieur le Professeur Arnaud Sauer,Merci de m'avoir fait l'honneur d'accepter de juger ce travail et d'y apporter votre regard critique d'expert en ophtalmo pédiatrie. Merci pour le temps que vous m'avez accordé et pour vos conseils. Recevez toute ma reconnaissance et ma gratitude. Aux praticiens de toute la France qui ont acceptés et ont pris le temps de me transmettre les dossiers de leurs patientsMerci pour la confiance que vous avez témoignée dans ce travail en acceptant d'y participer et merci pour les efforts que vous avez consacrez à cette aide qui nous était indispensable. ABSTRACT PURPOSE:Oculocutaneous albinism (OCA) is a heterogeneous group of genetic abnormalities that typically presents with congenital hypopigmentation and affects skin, hair and eyes. OCA type 1 is due to TYR mutations. R402Q is a thermosensible variant of the TY...
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