In-frame Val216-Ser217 deletion of KIT in mild piebaldism causes aberrant secretion and SCF response.

BACKGROUND: Piebaldism is a pigmentary disorder characterized by a white forelock and depigmented patches. Although the loss-of-function mutations in the KIT gene underlie the disease, the intracellular dynamics of the mutant KIT are largely unknown. We herein report a Japanese family with piebaldism in which the affected members showed a mild phenotype. OBJECTIVE: The objective of this study is to investigate the functions and intracellular dynamics of the mutant KIT protein. METHODS: We performed genetic analyses of the KIT gene using peripheral blood cells. We analyzed the intracellular localization of the mutant KIT protein in HEK293T cells transfected with wild-type (Wt) and/or mutant KIT genes. Immunoprecipitation analyses, immunoblotting and immunofluorescence studies were performed using antibodies against KIT and downstream signaling proteins. Glycosidase digestion analysis was performed to clarify the intracellular localization of KIT protein. RESULTS: A genetic analysis revealed a novel heterozygous mutation c.645_650delTGTGTC which results in the in-frame deletion of Val216 and Ser217 in the extracellular domain of KIT. Immunoprecipitation analyses confirmed that the wild and mutant KIT formed a heterodimer after treatment with stem cell factor (SCF); however, the phosphorylation of the downstream signaling factors was decreased. In an immunofluorescence study, the mutant KIT accumulated predominantly in the endoplasmic reticulum (ER) and was sparsely expressed on the cell surface. A glycosidase digestion study revealed that the mutant KIT is predominantly localized in the ER. CONCLUSION: These data reveal an aberrant function and intracellular localization of mutant KIT protein in piebaldism.

PARTIAL OCULOCUTANEOUS ALBINISM AND IMMUNODEFICIENCY SYNDROMES: TEN YEARS EXPERIENCE FROM A SINGLE CENTER IN TURKEY.

BACKGROUND AND AIM: Partial oculocutaneous albinism and immunodeficiency (OCA-ID) diseases are autosomal recessive syndromes characterized by partial hypopigmentation and recurrent infections. Moreover, some OCA-ID syndromes confer susceptibility to develop a life-threatening hyperinflammatory condition called hemophagocytic lymphohistiocytosis (HLH). We investigated the genetic, clinical and immunological characteristics of 20 OCA patients. MATERIAL AND METHODS: Herein, we present the clinical and immunological characteristics of 20 OCA patients who referred to the Department of Pediatric Immunology, Erciyes University Medical Faculty in Kayseri, Turkey between 2004 and 2014. RESULTS: Of the 20 OCA patients, 7 fulfilled diagnostic criteria for HLH, 9 showed defective functions of CD8 T cells and natural killer cells, and 8 received a definitive molecular diagnosis. Among the patients, we also report a patient diagnosed with two different genetic defects, in TYR and JAK3 genes, causing, respectively, OCA and ID. CONCLUSION: Our results illustrate the variability of clinical presentations and disease severity in OCA-ID patients, with consequent challenges in diagnosing and treating these patients.

Deletion of the SLUG (SNAI2) gene results in human piebaldism.

Slug is a zinc-finger neural crest transcription factor, encoded by the SLUG gene, which is critical for development of hematopoietic stem cells, germ cells, and melanoblasts in the mouse. In mouse, heterozygous and homozygous slug mutations result in anemia, infertility, white forehead blaze, and depigmentation of the ventral body, tail, and feet. This phenotype is very similar to the heterozygous W (KIT)-mutant mouse phenotype and to human piebaldism, which is characterized by a congenital depigmented patches and poliosis (white forelock). To investigate the possibility that some cases of human piebaldism might result from abnormalities of the human SLUG (SNAI2) gene, we carried out Southern blot analysis of the SLUG gene in 17 unrelated patients with piebaldism, who lack apparent KIT mutations. Three of these patients had evident heterozygous deletions of the SLUG gene encompassing the entire coding region. Real-time PCR confirmed the deletion in all cases. Fluoresence in situ hybridization (FISH) of genomic SLUG probes to metaphase chromosomes independently confirmed the deletion in one of the cases. These findings indicate that some cases of human piebaldism result from mutation of the SLUG gene on chromosome 8, and provide further strong evidence for the role of SLUG in the development of human melanocytes.

[The Griscelli-Prunieras syndrome: a case report]. / Síndrome de Griscelli-Prunieras: informe de un caso.

It is presented a six-year-old girl with silvered hair syndrome, of Griscelli-Prunieras variety; hereditary sickness with regressive autosomic and distinguished by partial albinism and leukocytic alterations. She presented the acute phase of the sickness distinguished by: hepatosplenomegaly, thrombocytopenia, lymphadenopathy generalized, and systematic infection; it is corroborated how a hemophagocytic syndrome; during her evolution developed pancerebellar syndrome. By laboratory were corroborated: decrease phagocytosis, degranulation 0%, decrease of globulins gamma, neutropenia, skin test of PPD and Candidin negatives, there were not find the giant inclusions in bone marrow leukocyte and peripheric blood that are feature of Chediak-Higashi syndrome. Another alteration that was the distribution of mote of melanin on the hair that in the Griscelli-Prunieras syndrome are six times bigger in the Chediak-Higashi syndrome.