A new autosomal dominant eye and lung syndrome linked to mutations in TIMP3 gene

To revisit the autosomal dominant Sorsby fundus dystrophy (SFD) as a syndromic condition including late-onset pulmonary disease. We report clinical and imaging data of ten affected individuals from 2 unrelated families with SFD and carrying heterozygous TIMP3 mutations (c.572A > G, p.Y191C, exon 5, in family 1 and c.113C > G, p.S38C, exon 1, in family 2). In family 1, all SFD patients older than 50 (two generations) had also a severe emphysema, despite no history of smoking or asthma. In the preceding generation, the mother died of pulmonary emphysema and she was blind after the age of 50. Her two great-grandsons (<20 years), had abnormal Bruch Membrane thickness, a sign of eye disease. In family 2, eye and lung diseases were also associated in two generations, both occurred later, and lung disease was moderate (bronchiectasis). This is the first report of a syndromic SFD in line with the mouse model uncovering the role of TIMP3 in human lung morphogenesis and functions. The TIMP3 gene should be screened in familial pulmonary diseases with bronchiectasis, associated with a medical history of visual loss. In addition, SFD patients should be advised to avoid tobacco consumption, to practice sports, and to undergo regular pulmonary examinations

Immunological and Metabolomic Impacts of Administration of Cry1Ab Protein and MON 810 Maize in Mouse

We have investigated the immunological and metabolomic impacts of Cry1Ab administration to mice, either as a purified protein or as the Cry1Ab-expressing genetically modified (GM) MON810 maize. Humoral and cellular specific immune responses induced in BALB/cJ mice after intra-gastric (i.g.) or intra-peritoneal (i.p.) administration of purified Cry1Ab were analyzed and compared with those induced by proteins of various immunogenic and allergic potencies. Possible unintended effects of the genetic modification on the pattern of expression of maize natural allergens were studied using IgE-immunoblot and sera from maize-allergic patients. Mice were experimentally sensitized (i.g. or i.p. route) with protein extracts from GM or non-GM maize, and then anti-maize proteins and anti-Cry1Ab–induced immune responses were analyzed. In parallel, longitudinal metabolomic studies were performed on the urine of mice treated via the i.g. route. Weak immune responses were observed after i.g. administration of the different proteins. Using the i.p. route, a clear Th2 response was observed with the known allergenic proteins, whereas a mixed Th1/Th2 immune response was observed with immunogenic protein not known to be allergenic and with Cry1Ab. This then reflects protein immunogenicity in the BALB/c Th2-biased mouse strain rather than allergenicity. No difference in natural maize allergen profiles was evidenced between MON810 and its non-GM comparator. Immune responses against maize proteins were quantitatively equivalent in mice treated with MON810 vs the non-GM counterpart and no anti-Cry1Ab–specific immune response was detected in mice that received MON810. Metabolomic studies showed a slight “cultivar” effect, which represented less than 1% of the initial metabolic information. Our results confirm the immunogenicity of purified Cry1Ab without evidence of allergenic potential. Immunological and metabolomic studies revealed slight differences in mouse metabolic profiles after i.g. administration of MON810 vs its non-GM counterpart, but no significant unintended effect of the genetic modification on immune responses was seen

Contribution of Whole-Genome Sequencing and Transcript Analysis to Decipher Retinal Diseases Associated with MFSD8 Variants.

Biallelic gene defects in MFSD8 are not only a cause of the late-infantile form of neuronal ceroid lipofuscinosis, but also of rare isolated retinal degeneration. We report clinical and genetic data of seven patients compound heterozygous or homozygous for variants in MFSD8, issued from a French cohort with inherited retinal degeneration, and two additional patients retrieved from a Swiss cohort. Next-generation sequencing of large panels combined with whole-genome sequencing allowed for the identification of twelve variants from which seven were novel. Among them were one deep intronic variant c.998+1669A&amp;gt;G, one large deletion encompassing exon 9 and 10, and a silent change c.750A&amp;gt;G. Transcript analysis performed on patients' lymphoblastoid cell lines revealed the creation of a donor splice site by c.998+1669A&amp;gt;G, resulting in a 140 bp pseudoexon insertion in intron 10. Variant c.750A&amp;gt;G produced exon 8 skipping. In silico and in cellulo studies of these variants allowed us to assign the pathogenic effect, and showed that the combination of at least one severe variant with a moderate one leads to isolated retinal dystrophy, whereas the combination in trans of two severe variants is responsible for early onset severe retinal dystrophy in the context of late-infantile neuronal ceroid lipofuscinosis

Management of albinism: French guidelines for diagnosis and care

Albinism is a worldwide genetic disorder caused by mutations in at least 20 genes, identified to date, that affect melanin production or transport in the skin, hair and eyes. Patients present with variable degrees of diffuse muco-cutaneous and adnexal hypopigmentation, as well as ocular features including nystagmus, misrouting of optic nerves and foveal hypoplasia. Less often, albinism is associated with blood, immunological, pulmonary, digestive and/or neurological anomalies. Clinical and molecular characterizations are essential in preventing potential complications. Disease-causing mutations remain unknown for about 25% of patients with albinism. These guidelines have been developed for the diagnosis and management of syndromic and non-syndromic forms of albinism, based on a systematic review of the scientific literature. These guidelines comprise clinical and molecular characterization, diagnosis, therapeutic approach and management

Br J Ophthalmol

AIM: Oculocutaneous albinism type 1 (OCA1) is due to TYR mutations. c.1205G>A/p.Arg402Gln (R402Q) is a thermosensitive variant of the TYR gene that has been reported to be responsible for mild forms of OCA1. The aim of our study was to define the phenotype associated with this variant. METHODS: In our retrospective series, among 268 patients diagnosed with OCA1, 122 (45.5%) harboured one pathogenic variant of TYR, and the R402Q variant ensured to be in trans by segregation analysis in 69 patients (25.7%), constituting the 'R402Q-OCA1' group. 146 patients harboured two pathogenic variants of the TYR gene other than R402Q. Clinical records were available for 119 of them, constituting the 'Classical-OCA1' group. RESULTS: Most R402Q-OCA1 patients presented with white or yellow-white hair at birth (71.43%), blond hair later (46.97%), a light phototype but with residual pigmentation (69.64%), and blue eyes (76.56%). Their pigmentation was significantly higher than in the classical-OCA1 group. All patients from the R402Q-OCA1 group presented with ocular features of albinism. However the prevalence of photophobia (78.13%) and iris transillumination (83.87%) and the severity scores of iris transillumination, retinal hypopigmentation and foveal hypoplasia were lower in the R402Q-OCA1 group. Visual acuity was higher in the R402Q-OCA1 group (0.38+/-0.21 logarithm of the minimum angle of resolution vs 0.76+/-0.24). Investigations concerning a possible additive effect of the c.575C>A/p.Ser192 (S192Y) variant of TYR in cis with R402Q, suggested by others, showed no significant impact on the phenotype. CONCLUSION: The R402Q variant leads to variable but generally mild forms of albinism whose less typical presentation may lead to underdiagnosis

Mutations in the m-AAA proteases AFG3L2 and SPG7 are causing isolated dominant optic atrophy

Objective To improve the genetic diagnosis of dominant optic atrophy (DOA), the most frequently inherited optic nerve disease, and infer genotype-phenotype correlations.MethodsExonic sequences of 22 genes were screened by new-generation sequencing in patients with DOA who were investigated for ophthalmology, neurology, and brain MRI.ResultsWe identified 7 and 8 new heterozygous pathogenic variants in SPG7 and AFG3L2. Both genes encode for mitochondrial matricial AAA (m-AAA) proteases, initially involved in recessive hereditary spastic paraplegia type 7 (HSP7) and dominant spinocerebellar ataxia 28 (SCA28), respectively. Notably, variants in AFG3L2 that result in DOA are located in different domains to those reported in SCA28, which likely explains the lack of clinical overlap between these 2 phenotypic manifestations. In comparison, the SPG7 variants identified in DOA are interspersed among those responsible for HSP7 in which optic neuropathy has previously been reported.ConclusionsOur results position SPG7 and AFG3L2 as candidate genes to be screened in DOA and indicate that regulation of mitochondrial protein homeostasis and maturation by m-AAA proteases are crucial for the maintenance of optic nerve physiology

Sci Rep

EMAP (Extensive Macular Atrophy with Pseudodrusen) is a maculopathy we recently described that shares pseudodrusen and geographic atrophy with Age-related Macular Disease (AMD). EMAP differs from AMD by an earlier age of onset (50-55 years) and a characteristic natural history comprising a night blindness followed by a severe visual loss. In a prospective case-control study, ten referral centers included 115 EMAP (70 women, 45 men) patients and 345 matched controls to appraise dietary, environmental, and genetic risk factors. The incidence of EMAP (mean 2.95/1.10(6)) was lower in Provence-Cote d'Azur with a Mediterranean diet (1.9/1.10(6)), and higher in regions with intensive farming or industrialized activities (5 to 20/1.10(6)). EMAP patients reported toxic exposure during professional activities (OR 2.29). The frequencies of common AMD complement factor risk alleles were comparable in EMAP. By contrast, only one EMAP patient had a rare AMD variant. This study suggests that EMAP could be a neurodegenerative disorder caused by lifelong toxic exposure and that it is associated with a chronic inflammation and abnormal complement pathway regulation. This leads to diffuse subretinal deposits with rod dysfunction and cone apoptosis around the age of 50 with characteristic extensive macular atrophy and paving stones in the far peripheral retina