Centronuclear myopathy in labrador retrievers: a recent founder mutation in the PTPLA gene has rapidly disseminated worldwide

Centronuclear myopathies (CNM) are inherited congenital disorders characterized by an excessive number of internalized nuclei. In humans, CNM results from ~70 mutations in three major genes from the myotubularin, dynamin and amphiphysin families. Analysis of animal models with altered expression of these genes revealed common defects in all forms of CNM, paving the way for unified pathogenic and therapeutic mechanisms. Despite these efforts, some CNM cases remain genetically unresolved. We previously identified an autosomal recessive form of CNM in French Labrador retrievers from an experimental pedigree, and showed that a loss-of-function mutation in the protein tyrosine phosphatase-like A (PTPLA) gene segregated with CNM. Around the world, client-owned Labrador retrievers with a similar clinical presentation and histopathological changes in muscle biopsies have been described. We hypothesized that these Labradors share the same PTPLA<sup>cnm</sup> mutation. Genotyping of an international panel of 7,426 Labradors led to the identification of PTPLA<sup>cnm</sup> carriers in 13 countries. Haplotype analysis demonstrated that the PTPLA<sup>cnm</sup> allele resulted from a single and recent mutational event that may have rapidly disseminated through the extensive use of popular sires. PTPLA-deficient Labradors will help define the integrated role of PTPLA in the existing CNM gene network. They will be valuable complementary large animal models to test innovative therapies in CNM

Phenotypic instability of patchwork mutation: an epigenetic effect?

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Les cellules souches des m´elanocytes de l’adulte

International audienceLes cellules souches des mélanocytes ont été récemment localisées dans le follicule pileux de la souris, dans un épaississement de la gaine épithéliale externe à la base de la partie permanente du follicule. La déplétion de la population des cellules souches et des progéniteurs des mélanocytes est responsable chez les individus âgés du grisonnement naturel des poils de la souris et des cheveux de l'homme. Les cellules souches des mélanocytes semblent être à l'origine de mélanomes malins cutanés. Quelques mutations spontanées ou fabriquées à façon accélèrent le processus de grisonnement avec l'âge. Ces mutations ont permis d'identifier des gènes et des voies de signalisation gouvernant l'établissement, le maintien et/ou la différenciation des cellules souches des mélanocytes. Dans cette revue, nous essayons de résumer les résultats récents sur les cellules souches des mélanocytes et définissons quelques questions importantes dans le domaine

Characterization of the melanocyte lineage in patchwork hair follicles

International audienceMice homozygous for the patchwork (pwk) recessive mutation are salt and pepper: their coat contains a mixture of unpigmented and fully pigmented hairs, but no partially pigmented hairs1. In the matrix of pwk/pwk unpigmented hair follicles, there are no mature melanocyte. This phenotype could be due to: (i) absence of the melanocyte stem cell (MSC) population, (ii) impaired differentiation of MSC into transit amplifying cells (TA cells), (iii) inhibition of TA cells proliferation and/or migration, or (iv) death of melanoblasts within the proliferative compartment. To discriminate between these hypotheses, we used transgenic mice expressing reporter genes for the melanocyte lineage, namely Dct-lacZ and Pax3GFP 2. We validated the Pax3GFP reporter strain by comparing its labelling of melanocyte lineage to Dct-lacZ’s. In pwk/pwk hair follicles, whatever the hair color, MSC and TA cells are present though in reduced number in the bulge and in the transitory portion respectively. In pwk/pwk unpigmented hair follicles, some TA cells reach the bulb region where they remain undifferentiated. By contrast, in the bulb of pwk/pwk pigmented hair follicles, TA cells are more numerous and differentiate into functional melanocytes. To test whether the impaired differentiation in the unpigmented hair follicles is related to the lower number of melanoblasts, we dissected pwk/pwk; Dct-lacZ/Dct-lacZ or pwk/pwk; Pax3GFP/+ and control hair follicles and counted cells of the melanocyte lineage within single hair follicles. Which process (survival, proliferation and/or migration) is deficient in the transit amplifying population is under investigation

Melanocyte precocious differentiation and ectopic localization in Notch conditional loss-of-function mice.

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RACK1, a clue to the diagnosis of cutaneous melanomas in horses

Chantier qualité GAInternational audienceBackgroundMelanocytic proliferations are common in horses but the diagnosis of malignancy is not always straightforward. To improve diagnosis and prognosis, markers of malignancy are needed. Receptor for activated C kinase 1 (RACK1) protein may be such a marker. RACK1 was originally found to characterize malignant melanocytic lesions in the Melanoblastoma-bearing Libechov minipig (MeLiM) and, later, in human patients. Our purpose was to investigate the value of RACK1 in the classification of cutaneous melanocytic proliferations in horses.ResultsUsing immunofluorescence, we report here that both MITF (Microphthalmia-associated transcription factor) and PAX3 (Paired box 3) allow the identification of melanocytic cells in horse skin samples. Importantly, RACK1 was detected in melanocytic lesions but not in healthy skin melanocytes. Finally, we found that RACK1 labeling can be used in horses to distinguish benign melanocytic tumors from melanomas. Indeed, RACK1 labeling appeared more informative to assess malignancy than individual histomorphological features.ConclusionsThis study confirms that horses provide an interesting model for melanoma genesis studies. It establishes MITF and PAX3 as markers of horse melanocytic cells. RACK1 emerges as an important marker of malignancy which may contribute to progress in the diagnosis of melanomas in both human and veterinary medicine

RACK1, a clue to the diagnosis of cutaneous melanomas in horses

Abstract Background Melanocytic proliferations are common in horses but the diagnosis of malignancy is not always straightforward. To improve diagnosis and prognosis, markers of malignancy are needed. Receptor for activated C kinase 1 (RACK1) protein may be such a marker. RACK1 was originally found to characterize malignant melanocytic lesions in the Melanoblastoma-bearing Libechov minipig (MeLiM) and, later, in human patients. Our purpose was to investigate the value of RACK1 in the classification of cutaneous melanocytic proliferations in horses. Results Using immunofluorescence, we report here that both MITF (Microphthalmia-associated transcription factor) and PAX3 (Paired box 3) allow the identification of melanocytic cells in horse skin samples. Importantly, RACK1 was detected in melanocytic lesions but not in healthy skin melanocytes. Finally, we found that RACK1 labeling can be used in horses to distinguish benign melanocytic tumors from melanomas. Indeed, RACK1 labeling appeared more informative to assess malignancy than individual histomorphological features. Conclusions This study confirms that horses provide an interesting model for melanoma genesis studies. It establishes MITF and PAX3 as markers of horse melanocytic cells. RACK1 emerges as an important marker of malignancy which may contribute to progress in the diagnosis of melanomas in both human and veterinary medicine.</p

Genetic interaction between a maternal factor and the zygotic genome controls the intestine length in PRM/Alf mice

Genetic interaction between a maternal factor and the zygotic genome controls the intestine length in PRM/Alf mice. Physiol Genomics 16: 82–89, 2003. First published October 14, 2003; 10.1152/physiolgenomics.00106.2003.—Postoperative management of small and large bowel resections would be helped by use of intestinotrophic molecules. Here, we present a mouse inbred strain called PRM/Alf that is characterized by a selective intestinal lengthening. We show that PRM/Alf intestine is one-third longer compared with other inbred strains. The phenotype is acquired mostly during the postnatal period, before weaning. Its genetic determinism is polygenic, and involves a strong maternal effect. Cross-fostering experiments revealed that the dam’s genotype acts synergistically with the offspring’s genotype to confer the longest intestine. Moreover, genes in the offspring have a direct effect on intestine length. Possible involvement of milk growth factors and identification of candidate genes are discussed