Neuronal ceroid lipofuscinoses (NCLs) represent the most common group of inherited progressive encephalopathies in children. They are characterized by progressive loss of vision, mental and motor deterioration, epileptic seizures, and premature death. Rare adult forms of NCL with late onset are known as Kufs’ disease. Loci underlying these adult forms remain unknown due to the small number of patients and genetic heterogeneity. Here we confirm that a late-onset form of NCL recessively segregates in US and French pedigrees of American Staffordshire Terrier (AST) dogs. Through combined association, linkage, and haplotype analyses, we mapped the disease locus to a single region of canine chromosome 9. We eventually identified a worldwide breed-specific variant in exon 2 of the Arylsulfatase G ( ARSG ) gene, which causes a p.R99H substitution in the vicinity of the catalytic domain of the enzyme. In transfected cells or leukocytes from affected dogs, the missense change leads to a 75% decrease in sulfatase activity, providing a functional confirmation that the variant might be the NCL-causing mutation. Our results uncover a protein involved in neuronal homeostasis, identify a family of candidate genes to be screened in patients with Kufs' disease, and suggest that a deficiency in sulfatase is part of the NCL pathogenesis.

Background: A mutation in the sarcomeric gene coding for the myosin-binding protein C gene has been identified in a colony of Maine Coon cats with hypertrophic cardiomyopathy (MyBPC3-A31P mutation). However, the close correlation between genotype and phenotype (left ventricular hypertrophy [LVH] and dysfunction) has never been assessed in a large population, particularly in heterozygous (Hetero) cats.Objectives: To investigate LV morphology and function with echocardiography and tissue Doppler imaging (TDI) in a population of Maine Coon cats tested for the MyBPC3-A31P mutation with focus on Hetero animals.Animals: Ninety-six Maine Coon cats. Methods: Prospective observational study. Cats were screened for the MyBPC3-A31P mutation and examined with both echocardiography and 2-dimensional color TDI.Results: Fifty-two out of 96 cats did not have the mutation (wild-type genotype, Homo WT), 38/96 and 6/96 were Hetero-and homozygous-mutated (Homo M) cats, respectively. Only 11% of Hetero cats (4/38) had LVH and 29% (10/34) of Hetero cats without LVH were 44 years old (4.1-11.5 years). LVH was also detected in 2 Homo WT cats (4%). A significantly decreased (P o .05) longitudinal E/A (ratio between early and late diastolic myocardial velocities) in the basal segment of the interventricular septum was observed in Hetero cats without LVH (n 5 34) compared with Homo WT cats without LVH (n 5 50), thus confirming that the Hetero status is associated with regional diastolic dysfunction (P o .05).Conclusions: The heterozygous status is not consistently associated with LVH and major myocardial dysfunction. Moreover, Homo WT cats can also develop LVH, suggesting that other genetic causes might be implicated.

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Patients with deficiency in ferrochelatase (FECH), the last enzyme of the heme biosynthetic pathway, experience a painful type of skin photosensitivity called erythropoietic protoporphyria (EPP), which is caused by the excessive production of protoporphyrin IX (PPIX) by erythrocytes. Controversial results have been reported regarding hematologic status and iron status of patients with EPP. We thoroughly explored these parameters in Fech m1Pas mutant mice of 3 different genetic backgrounds. FECH deficiency induced microcytic hypochromic anemia without ringed sideroblasts, little or no hemolysis, and no erythroid hyperplasia. Serum iron, ferritin, hepcidin mRNA, and Dcytb levels were normal. The homozygous Fech m1Pas mutant involved no tissue iron deficiency but showed a clear-cut redistribution of iron stores from peripheral tissues to the spleen, with a concomitant 2-to 3-fold increase in transferrin expression at the mRNA and the protein levels. Erythrocyte PPIX levels strongly correlated with serum transferrin levels. At all stages of differentiation in our study, transferrin receptor expression in bone marrow erythroid cells in Fech m1Pas was normal in mutant mice but not in patients with iron-deficiency anemia. Based on these observations, we suggest that oral iron therapy is not the therapy of choice for patients with EPP and that the PPIXliver transferrin pathway plays a role in the orchestration of iron distribution between peripheral iron stores, the spleen, and the bone marrow. IntroductionErythropoietic protoporphyria (EPP; Mendelian Inheritance in Man [MIM] 177000) is an inherited disorder caused by partial deficiency of ferrochelatase (FECH; EC 4.99.1.1.), the last enzyme of the heme biosynthetic pathway. 1 FECH is an inner membrane mitochondrial enzyme catalyzing the insertion of ferrous iron into protoporphyrin IX (PPIX) to form heme. FECH deficiency in bone marrow erythroid cells is responsible for the primary overproduction of PPIX, leading to an accumulation of protoporphyrin in the bone marrow, plasma, erythrocytes, skin, bile, and feces. 2 Because of its hydrophobic nature, PPIX can be removed from the body only through the liver, where it is secreted into bile and then is excreted by fecal elimination. 3 More than100 mutations in the FECH gene, including missense, nonsense, splicing, deletions, and insertions, have been identified in EPP families (Human Gene Mutation Database, http:// archive.uwcm.ac.uk/uwcm/mg/hgmd0.html). Usually, EPP is inherited as an autosomal pseudodominant disorder, and clinical penetrance is mainly modulated by the presence of a common intronic single-nucleotide polymorphism (SNP), IVS3-48C, in trans to a dominant mutation. 4,5 The most common clinical manifestation of EPP is lifelong acute photosensitivity of sun-exposed skin appearing in early childhood. 6 Although EPP is generally a benign disease, hepatic complications such as cholelithiasis or, in rare cases (approximately 2%), rapid fatal liver disease with cirrhosis may occur. [7][8][9] Chronic liver disease i...

A variety of cat breeds have been developed via novelty selection on aesthetic, dermatological traits, such as coat colors and fur types. A recently developed breed, the lykoi (a.k.a. werewolf cat), was bred from cats with a sparse hair coat with roaning, implying full color and all white hairs. The lykoi phenotype is a form of hypotrichia, presenting as a significant reduction in the average numbers of follicles per hair follicle group as compared to domestic shorthair cats, a mild to severe perifollicular to mural lymphocytic infiltration in 77% of observed hair follicle groups, and the follicles are often miniaturized, dilated, and dysplastic. Whole genome sequencing was conducted on a single lykoi cat that was a cross between two independently ascertained lineages. Comparison to the 99 Lives dataset of 194 non-lykoi cats suggested two variants in the cat homolog for Hairless (HR) (HR lysine demethylase and nuclear receptor corepressor) as candidate causal gene variants. The lykoi cat was a compound heterozygote for two loss of function variants in HR, an exon 3 c.1255_1256dupGT (chrB1:36040783), which should produce a stop codon at amino acid 420 (p.Gln420Serfs*100) and, an exon 18 c.3389insGACA (chrB1:36051555), which should produce a stop codon at amino acid position 1130 (p.Ser1130Argfs*29). Ascertainment of 14 additional cats from founder lineages from Canada, France and different areas of the USA identified four additional loss of function HR variants likely causing the highly similar phenotypic hair coat across the diverse cats. The novel variants in HR for cat hypotrichia can now be established between minor differences in the phenotypic presentations.

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BackgroundSeven donkey breeds are recognized by the French studbook. Individuals from the Pyrenean, Provence, Berry Black, Normand, Cotentin and Bourbonnais breeds are characterized by a short coat, while those from the Poitou breed (Baudet du Poitou) are characterized by a long-hair phenotype. We hypothesized that loss-of-function mutations in the FGF5 (fibroblast growth factor 5) gene, which are associated with a long-hair phenotype in several mammalian species, may account for the special coat feature of Poitou donkeys. To the best of our knowledge, mutations in FGF5 have never been described in Equidae.MethodsWe sequenced the FGF5 gene from 35 long-haired Poitou donkeys, as well as from a panel of 67 short-haired donkeys from the six other French breeds and 131 short-haired ponies and horses.ResultsWe identified a recessive c.433_434delAT frameshift deletion in FGF5, present in Poitou and three other donkey breeds and a recessive nonsense c.245G > A substitution, present in Poitou and four other donkey breeds. The frameshift deletion was associated with the long-hair phenotype in Poitou donkeys when present in two copies (n = 31) or combined with the nonsense mutation (n = 4). The frameshift deletion led to a stop codon at position 159 whereas the nonsense mutation led to a stop codon at position 82 in the FGF5 protein. In silico, the two truncated FGF5 proteins were predicted to lack the critical β strands involved in the interaction between FGF5 and its receptor, a mandatory step to inhibit hair growth.ConclusionsOur results highlight the allelic heterogeneity of the long-hair phenotype in donkeys and enlarge the panel of recessive FGF5 loss-of-function alleles described in mammals. Thanks to the DNA test developed in this study, breeders of non-Poitou breeds will have the opportunity to identify long-hair carriers in their breeding stocks.Electronic supplementary materialThe online version of this article (doi:10.1186/s12711-014-0065-5) contains supplementary material, which is available to authorized users.