LYST Gene Research Articles

Clinical aspects of hereditary spastic paraplegias

Hereditary spastic paraplegias (HSPs) were characterized by progressive leg spasticity with various additional symptoms as follows: peripheral neuropathy, cerebellar ataxia, extrapyramidal symptoms, mental impairment, optic atrophy, pigmental retinopathy, and so on. Many genetic loci (SPG1-72) and more than 50 genes were identified so far. Recently, we identified the causative gene, C12orf65, that was reported the gene for Leigh syndrome, for autosomal recessive spastic paraplegia with optic atrophy and neuropathy (SPG55). We also identified the mutation of the LYST gene, that is causative gene for Chediak-Higashi syndrome, for the autosomal recessive complicated spastic paraplegia with cerebellar ataxia and neuropathy. In this review, we introduced clinical symptoms about our cases suffered from SPG4, SPG11, SPG55 and complicated spastic paraplegia due to adult Chediak-Higashi syndrome. SPG4, that is usually exhibits pure spastic paraplegia, but our case shows mental impairment and variable age of onset. HSPs are clinically and genetically heterogeneous syndromes, i. e., same gene mutations with different clinical manifestations or same clinical presentations with different gene mutations. We should perform board range differential diagnosis and analysis of numerous causative genes to the patients with spastic paraplegia, especially autosomal recessive trait.

Chediak-Higashi syndrome: pathognomonic feature

A 2-year-old girl presented to us with recurrent infections, hepatosplenomegaly, and photophobia. On examination she had blond hair with a metallic sheen. The blood smear showed giant lysosomes in the white blood cells (figure) and we diagnosed Chediak-Higashi syndrome, a rare autosomal recessive disease (gene CHS1/LYST at 1q42.1-2). There have been around 200 cases reported, and giant cytoplasmic granules are pathognomonic. Death often occurs before the age of 7 years because of the so-called accelerated phase, with hepatosplenomegaly, lymphadenopathy, and pancytopenia or severe recurrent bacterial infections. The laboratory diagnosis was supported by partial oculocutaneous albinism and typical microscopic granules in hair shafts. A new mutation was identified and our patient was found to be homozygous for a sequence change in the LYST gene: p.G3583R:c.10747G>. She currently waits for a compatible haemopoietic cell transplantation donor. Her parents and brother are not HLA-identical. Our patient is now 7 years old, and is well, without serious infections, and with normal neurological function, which might be related to a milder clinical phenotype.

The Accelerated Phase of Chediak-Higashi Syndrome: The Importance of Hematological Evaluation

To the Editor Chediak-Higashi syndrome is a rare autosomal recessive disease that was first described in 1943 by Bequez-Cesar in 3 siblings that bore the primary clinical features. In 1952 Chediak (a Cuban hematologist) and in 1954 Higashi (a Japanese pediatrician) described a series of cases characterized by misdistribution of myeloperoxidase in the patients’ neutrophilic granules [1,2]. Mean age of onset is 5.85 years; however, most patients die before age 10 years. In patients that do survive beyond childhood the neurologic problems persist and/or increase in magnitude [3]. Most cases are diagnosed clinically based on partial albinism and recurrent pyogenic infections. Both of our patients had hypopigmentation of the skin with patchy grey hairs, mild coagulation defects identified via the presence of petechial rashes on the skin, and a history of recurrent infections since birth. The characteristic hematological finding is massive lysosomal inclusions in all white cells, formed via a combined process of fusion, cytoplasmic injury, and phagocytosis due to a microtubular defect [3]. These granules exhibit both azurophilic and specific granular markers (Figure 1), and are strongly myeloperoxidase positive. Approximately 85% of cases develop a fatal accelerated phase characterized by pancytopenia, hemophagocytosis, and marked infiltration of organs by lymphocytes, leading to multi-organ dysfunction [4]. Herein we present 2 cases in the accelerated phase of Chediak-Higashi syndrome. Both were born to apparently healthy non-consanguineous parents. Figure 1 Large intracytoplasmic granules in a granulocytic cell (Giemsa stained bone marrow aspirate film; 1000×). Case 1 was a 2.5-year-old female that presented with a 6-month history of abdominal distension and moderate pallor, and a 5-d history of cough. General physical examination showed that she was thin built, and had normal facies with patchy grey hair and hypopigmentation of the skin. Systemic examination showed hepatosplenomegaly; the liver was 6 cm below the right costal margin and the spleen was 13 cm below the left costal margin. The cardiovascular and respiratory systems were normal. She also had bilateral cervical lymphadenopathy. Case 2 was a 3-year-old female that presented with a 3-month history of fever, and a 1-month history of abdominal distension, itching over the body, and moderate pallor. Physical examination showed patchy gray hair and generalized albinism with petechial spots on the thighs and abdomen. The patient weighed 7.6 kg, was of average build with normal facies and significant hepatosplenomegaly; the liver was 4 cm below the right costal margin and the spleen was 7 cm below the left costal margin. Both patients underwent bone marrow aspiration due to peripheral blood pancytopenia and organomegaly. Hemogram findings in cases 1 and 2 were, respectively, as follows: Hb: 4.2 g/dL and 3.9 g/dL; WBC: 4 × 109/L and 3 × 109/L; platelet count: 8 × 109/L and 6 × 109/L. Bone marrow aspiration findings in both cases are shown in the Table 1. Both patients had hematological findings characteristic of the accelerated phase of Chediak-Higashi syndrome-peripheral blood pancytopenia and marked hemophagocytosis (Figure 2) on bone marrow aspirate, along with lymphocyte infiltration on trephine biopsy section. Both cases were negative for HIV, CMV, and EBV serology. Table 1 Bone marrow aspirate findings in cases 1 and 2. Figure 2 Hemophagocytosis in bone marrow smear (Giemsa stain; 1000×). The genetic hallmark of Chediak-Higashi syndrome is mutations in the CHS1/LYST gene. The gene product is known to regulate lysosomal organelle function and size. The mutations could not be characterized in the presented cases because the DNA material for analysis was insufficient in one case and the other died due to the fulminant accelerated phase before hematological diagnosis was established. It is well known that Chediak-Higashi syndrome patients with deletions in the LYST gene usually present with a fulminant accelerated phase early in life, whereas those with missense mutations have a relatively better prognosis characterized by the absence of an accelerated phase and no neurological involvement [5]. The hematological findings of pancytopenia and hemophagocytosis suggest a possible deletion in the LYST gene in both of the presented cases, but ethnicity data and complete DNA analysis are needed to further substantiate the findings; nonetheless, both cases presented with the characteristic clinical and hematological profiles diagnostic of Chediak-Higashi syndrome. Careful examination of peripheral blood film in suspected cases can facilitate early diagnosis and further evaluation. In addition, recognition of early cytopenias should alert clinicians and hematologists of an impending accelerated phase. Furthermore, bone marrow aspiration is a useful diagnostic procedure for identifying tissue hemophagocytosis in such patients. Conflict of Interest Statement The authors of this paper have no conflicts of interest, including specific financial interests, relationships, and/ or affiliations relevant to the subject matter or materials included.

A New Method for Rapid Detection of the Mutant Allele for Chediak-Higashi Syndrome in Japanese Black Cattle

Chediak-Higashi syndrome (CHS) is an autosomal recessive hereditary disorder in Japanese Black cattle, caused by a mutation of the Lyst gene. So far, the mutation has been detected by PCR-restriction fragment length polymorphism (PCR-RFLP) analysis. However, this method is disadvantaged by its low-throughput performance. Here, we report an alternative method involving real-time PCR with TaqMan minor groove binder probes, which shortens the total assay time by more than 120 min, analyzing 10 samples in a duplicated manner. Using this method, we examined 102 Japanese Black cattle and found that 8.8% of the cattle were CHS-carriers. These data indicate that our technique is useful for routine diagnostic testing for CHS in Japanese Black cattle.

SAP and XIAP deficiency in hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is a multisystem inflammatory disorder due to cytokine overproduction from excessively activated lymphocytes and macrophages. HLH has been divided into two subgroups: primary HLH and secondary HLH. Primary HLH includes PRF1, UNC13D, STX11, STXBP2, RAB27A, LYST, SH2D1A and XIAP gene mutations; and secondary HLH is associated with infections, malignancies and autoimmune diseases. Among primary HLH-related genes, SH2D1A and XIAP are genetically responsible for X-linked lymphoproliferative syndrome (XLP) due to signaling-lymphocytic-activation-molecule-associated protein (SAP) and XIAP deficiencies, respectively. XLP is characterized by extreme vulnerability to Epstein-Barr virus infection. The major clinical manifestations of XLP consist of HLH (60%), lymphoproliferative disorder (30%) and dysgammaglobulinemia (30%). Analysis of clinical phenotypes of XLP patients suggests that XLP predominantly shows familial HLH phenotypes, whereas some XLP patients present sporadic HLH. For many decades, clinicians and investigators have been concerned with possible XLP in young boys presenting with Epstein-Barr-virus-associated HLH. This review aims to describe the new knowledge about XLP and to draw the attention of the pediatrician to XLP, which should be differentiated from other forms of HLH.

Screening for cytotoxic defects with flow cytometric detection of CD107α on natural killer cells and cytotoxic lymphocyte cells

To establish a novel flow cytometry-based assay for measuring the expression of lysosomal-associated membrane protein 1 (LAMP-1, CD107α) on the cell surface of natural killer (NK) cells and cytotoxic T lymphocyte (CTL) and evaluate the screening value of this assay for cytotoxic defects-related diseases such as familial hemophagocytic lymphopro-liferative (FHL) syndrome. Three suspected Chediak-Higashi Syndrome (CHS) patients, three suspected FHL patients and 10 healthy children were enrolled in the study from October 2010 to June 2011. Their PBMCs were separated and activated overnight with IL-2. After the granule release of NK cells activated by phytohemagglutinin (PHA) and CD8+T cells by anti-CD3, the CD107α expression were analyzed by flow cytometry. The peripheral blood DNA and RNA of the patients were extracted to analyze the pathogenic genes via DNA-PCR/RT-PCR and direct sequencing. The CD107α expression on CTL in the ten healthy children significantly increased after activation by anti-CD3 [(0.18 ± 0.07)% vs. (4.47 ± 2.36)%, P < 0.05] and NK cells after activation by PHA [(0.27 ± 0.07)% vs. (5.80 ± 2.83)%, P < 0.05]. The frequency of CD107α-expression NK cells in three suspected CHS after activation was significantly elevated when compared with the healthy control [0.5%, 0.6% vs. (5.80 ± 2.83)%] except patient 2. After the anti-CD3 activation, the frequency of CD107α expression on CTL cells also showed no significant difference [0.3%, 0.9%, 0.2% vs. (4.47 ± 2.36)%] in three patients. All of their mean fluorescence intensity (MFI) showed the same trend. Patient 1 and 3 were identified to have LYST mutations (Patient 1: c.5411-5414 del TTTC, L1741fsX1758 and c.7975 C > T, R2596X; Patient 3: c.4863G > A, R1563H and c.5392-5393delAA, E1739fsX1756). There was no mutation identified in the LYST gene for patient 2. CD107α expression of NK cells and CTL in the suspected FHL patients and in mirror of these findings, no underlying gene variation of PRF, MUNC13-4 and STX11 were identified. We developed a method to quantitatively assess cytotoxicity of the NK cells and CTL by measuring the expression of CD107α on the cell membrane, which appeared to be an effective and rapid screening test for cytotoxic defects-related diseases such as FHL and other HLH secondary to primary immunodeficiency.

Acclerated phase of Chediak-Higashi syndrome-a case report with review of literature

The Chediak Higashi Syndrome (CHS) is a rare autosomal recessive disease characterized by partial oculo-cutaneous albinism, frequent pyogenic infections, presence of giant granules in leucocytes and other granule containing cells. Associated findings include silvery hair, photophobia, horizontal and rotatory nystagmus, hepatosplenomegaly and peripheral neuropathy. Mutation of the LYST gene defines the syndrome. The first case of Chediak Higashi Syndrome was reported by Bequez-cesar in 1943. Since its first description, around 170 cases have been reported in the literature till date and 10 cases have been reported from India.

Subtle differences in CTL cytotoxicity determine susceptibility to hemophagocytic lymphohistiocytosis in mice and humans with Chediak-Higashi syndrome

AbstractPerforin-mediated cytotoxicity is important for controlling viral infections, but also for limiting immune reactions. Failure of this cytotoxic pathway leads to hemophagocytic lymphohistiocytosis (HLH), a life-threatening disorder of uncontrolled T-cell and macrophage activation. We studied susceptibility to HLH in 2 mouse strains (souris and beigeJ) and a cohort of patients with partial defects in perforin secretion resulting from different mutations in the LYST gene. Although both strains lacked NK-cell cytotoxicity, only souris mice developed all clinical and histopathologic signs of HLH after infection with lymphocytic choriomeningitis virus. The 2 strains showed subtle differences in CTL cytotoxicity in vitro that had a large impact on virus control in vivo. Whereas beigeJ CTLs eliminated lymphocytic choriomeningitis virus infection, souris CTLs failed to control the virus, which was associated with the development of HLH. In LYST-mutant patients with Chediak-Higashi syndrome, CTL cytotoxicity was reduced in patients with early-onset HLH, whereas it was retained in patients who later or never developed HLH. Thus, the risk of HLH development is set by a threshold that is determined by subtle differences in CTL cytotoxicity. Differences in the cytotoxic capacity of CTLs may be predictive for the risk of Chediak-Higashi syndrome patients to develop HLH.

A novel single point mutation of the LYST gene in two siblings with different phenotypic features of Chediak Higashi syndrome

Chediak Higashi syndrome (CHS) is an autosomal-recessive disorder characterized by oculocutaneous albinism, recurrent infections and a progressive primary neurological disease. Here, we describe two siblings with CHS due to a novel homozygous R1836X mutation in the LYST gene associated with loss of NK cell degranulation and cytotoxicity. While one sibling was born with fair skin and hair and died of hemophagocytic lymphohistiocytosis (HLH) at 5 months of age, the other sibling had dark black hair and skin and developed HLH at the age of 4 years.

Digital Quantification of Human Eye Color Highlights Genetic Association of Three New Loci

Previous studies have successfully identified genetic variants in several genes associated with human iris (eye) color; however, they all used simplified categorical trait information. Here, we quantified continuous eye color variation into hue and saturation values using high-resolution digital full-eye photographs and conducted a genome-wide association study on 5,951 Dutch Europeans from the Rotterdam Study. Three new regions, 1q42.3, 17q25.3, and 21q22.13, were highlighted meeting the criterion for genome-wide statistically significant association. The latter two loci were replicated in 2,261 individuals from the UK and in 1,282 from Australia. The LYST gene at 1q42.3 and the DSCR9 gene at 21q22.13 serve as promising functional candidates. A model for predicting quantitative eye colors explained over 50% of trait variance in the Rotterdam Study. Over all our data exemplify that fine phenotyping is a useful strategy for finding genes involved in human complex traits.

LystMutation in Mice Recapitulates Iris Defects of Human Exfoliation Syndrome

Human eyes with exfoliation syndrome (XFS) exhibit a distinctive pattern of iris transillumination defects that are recapitulated in Lyst mutant mice carrying the beige allele. The purpose of this study was to determine the anatomic basis for Lyst-mediated transillumination defects, test whether Lyst mutant mice develop other features of XFS, and describe the molecular basis of the beige mutation. Lyst mutant mice and strain-matched controls were compared by clinical, histologic, immunohistochemical, and molecular genetic analyses. Slit-lamp examination showed that Lyst mutant mice uniformly exhibit XFS-like transillumination defects. Histologic analysis showed that these defects correlate with a sawtooth morphology of the iris pigment epithelium. Lyst mutant mice also produce an exfoliative-like material and exhibit pronounced pigment dispersion. Despite these insults, Lyst mutation does not cause increased intraocular pressure or optic nerve damage in the C57BL/6J genetic background. Sequence analysis identified that the beige mutation is predicted to delete a single isoleucine from the WD40 domain of the LYST protein, suggesting that this mutation is likely to disrupt a protein-protein interaction. Lyst mutant eyes exhibit multiple features of XFS. Recent human genetic association studies have identified changes occurring in the LOXL1 gene as an important risk factor for XFS but also indicated that other factors contributing to risk likely exist. These results demonstrated that mutation of the Lyst gene can produce ocular features of human XFS and suggested that LYST or LYST-interacting genes may contribute to XFS.

Altered Composition and Secretion of Lysosome‐Derived Compartments in Dictyostelium AP‐3 Mutant Cells

Genetic alteration of the adaptor protein (AP)-3 complex is responsible for the type 2 Hermansky-Pudlak syndrome, a lysosomal storage disease similar to the Chediak-Higashi syndrome (CHS). AP-3 presumably participates in the biogenesis of late endosomal compartments and may also be critical for the regulated secretion of lysosomes by specialized cells. Here, Dictyostelium discoideum cells defective for the mu3 subunit of the AP-3 complex were used and their phenotype analyzed. In mu3 mutant cells, endosomal maturation and lysosome secretion were markedly slower than that in wild-type cells. This phenotype is similar to that reported previously in lvsB mutant cells where the ortholog of the LYST gene, involved in CHS, is mutated. Detailed analysis revealed however significant differences between these two isogenic mutant cells: in lvsB mutant cells, the primary defect is an inefficient biogenesis of otherwise normal secretory lysosomes, while in mu3 mutant cells, the biogenesis and also the composition and the fusion properties of secretory lysosomes are affected. These results suggest that in D. discoideum, AP-3 controls both the efficiency and the specificity of postlysosome maturation, which represent two critical elements in the control of lysosome secretion.

A missense mutation in the WD40 domain of murine Lyst is linked to severe progressive Purkinje cell degeneration

Disturbance of intracellular trafficking plays a major role in several neurodegenerative disorders including Alzheimer or Parkinson's disease. The Chediak-Higashi syndrome (CHS), a life-threatening autosomal recessive disease with frequent mutations in the LYST gene, and its animal model, the beige mouse, are both characterized by lysosomal defects with accumulation of giant lysosomes. Clinically they manifest as hypopigmentation, abnormal bleeding and increased susceptibility to infection with various degrees of involvement of the nervous system. In the course of a recessive N-ethyl-N-nitrosurea (ENU) mutagenesis screen, we identified the first murine missense mutation in the lysosomal trafficking regulator gene (Lyst(Ing3618)) located at a highly conserved position in the WD40 protein domain. Nearly all described human Lyst alleles lead to protein truncation and fatal childhood CHS. Only four different missense mutations have been reported in patients with adolescent or adult forms of CHS involving the nervous system. Interestingly, the Lyst(Ing3618) model presents with a predominant neurodegenerative phenotype with progressive degeneration and loss of Purkinje cells and lacks severe impairment of the immune system. Therefore, the Lyst(Ing3618 )allele could represent a new model for adult CHS with neurological impairment. It could also provide an important tool to elucidate the role of neuronal lysosomal trafficking in the pathophysiology of neurodegeneration.

Primary immunodeficiency diseases: An update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee Meeting in Budapest, 2005

Although relatively rare, primary immunodeficiency diseases (PIDs) provide an excellent window into the functioning of the immune system. In the late 1960s, observations on these diseases, with their associated infections and genetics, bisected the immune system into humoral immunity and cell-mediated immunity. These diseases also represent a challenge in their diagnosis and treatment. Beginning in 1970, a unified nomenclature for the then-known PIDs was created by a committee convoked by the World Health Organization. Since then, and later under the aegis of the International Union of Immunological Societies, an international committee of experts has met every 2 to 3 years to update the classification of PIDs. During the past 15 years, the molecular basis of more than 120 PIDs has been elucidated. This update results from the latest meeting of this committee in Budapest, Hungary, in June 2005, which followed 2 1/2 days of scientific discussions. As a result of this work, new entities have been included, and the nomenclature of some PIDs (specifically of the various forms of class-switch recombination defects, previously known as hyper-IgM syndromes) has been changed.

Grey, a novel mutation in the murine Lyst gene, causes the beige phenotype by skipping of exon 25

The murine beige mutant phenotype and the human Chediak-Higashi syndrome are caused by mutations in the murine Lyst (lysosomal trafficking regulator) gene and the human CHS gene, respectively. In this report we have analyzed a novel murine mutant Lyst allele, called Lyst(bg-grey), that had been found in an ENU mutation screen and named grey because of the grey coat color of affected mice. The phenotype caused by the Lyst(bg-grey) mutation was inherited in a recessive fashion. Melanosomes of melanocytes associated with hair follicles and the choroid layer of the eye, as well as melanosomes in the neural tube-derived pigment epithelium of the retina, were larger and irregularly shaped in homozygous mutants compared with those of wild-type controls. Secretory vesicles in dermal mast cells of the mutant skin were enlarged as well. Test crosses with beige homozygous mutant mice (Lyst(bg)) showed that double heterozygotes (Lyst(bg)/Lyst(bg-grey)) were phenotypically indistinguishable from either homozygous parent, demonstrating that the ENU mutation was an allele of the murine Lyst gene. RT-PCR analyses revealed the skipping of exon 25 in Lyst(bg-grey) mutants, which is predicted to cause a missense D2399E mutation and the loss of the following 77 amino acids encoded by exon 25 but leave the C-terminal end of the protein intact. Analysis of the genomic Lyst locus around exon 25 showed that the splice donor at the end of exon 25 showed a T-to-C transition point mutation. Western blot analysis suggests that the Lyst(bg-grey) mutation causes instability of the LYST protein. Because the phenotype of Lyst(bg) and Lyst(bg-grey) mutants is indistinguishable, at least with respect to melanosomes and secretory granules in mast cells, the Lyst(bg-grey) mutation defines a critical region for the stability of the murine LYST protein.

Identification of genes responsible for hereditary diseases in Japanese beef cattle

ABSTRACTIn the breeding of domestic animals, selection of economically desired traits has been the most important consideration for the improvement of animals, but excluding negative factors in animal production, such as causative genes for hereditary diseases, is also required for the genetic improvement of domestic animals. The incidence of various hereditary diseases has been reported in Japanese beef cattle and these diseases have caused serious problems in the breeding and raising of healthy beef cattle. This article reviews the identification of causative genes for the following three hereditary diseases in Japanese beef cattle: (i) Chediak–Higashi syndrome; (ii) renal tubular dysplasia; and (iii) bovine chondrodysplastic dwarfism. Chediak–Higashi syndrome is a hereditary bleeding disorder reported in Japanese black cattle. To identify the cause of this disease, we cloned and sequenced the bovine LYST gene, which has been found to be involved in Chediak–Higashi syndrome in humans, and found that an amino acid substitution of histidine to arginine at amino acid residue 2015 is the causative mutation in the cattle disease. Renal tubular dysplasia is a hereditary disease of Japanese black cattle showing renal failure and growth retardation. We mapped the locus for this disease to the 4 cM region of bovine chromosome 1 by linkage analysis and found a large deletion in this region. The deleted region contained the PCLN1 gene encoding a tight‐junction protein of renal epithelial cells, and we concluded that deletion of the PCLN1 gene is responsible for the disease. Bovine chondrodysplastic dwarfism is a hereditary disease of Japanese brown cattle, displayed by short limbs and joint abnormalities. We mapped the locus for the disease to a region of bovine chromosome 6 by linkage analysis. By constructing YAC and BAC contigs covering this region and sequence analysis, we identified a novel gene (LIMBIN), which plays an essential role in bone formation in this region, and found two mutations responsible for the disease. The identification of these mutations provided the basis for DNA‐based diagnostic systems for these three diseases, and after development of the diagnosis systems, the incidences of these hereditary diseases have dramatically decreased.

Chediak‐Higashi syndrome: four cases from Northern Finland

Chediak-Higashi syndrome (CHS) is a rare multiorgan disease entity with autosomal recessive inheritance characterized by oculocutaneous albinism, bleeding tendency, recurrent bacterial infections and various neurological symptoms. Intracellular vesicle formation is deficient, resulting in giant granules in many cells, e.g. giant melanosomes in the melanocytes. Diagnosis has been based on morphological examination of peripheral blood and bone marrow, with giant granules seen in cells of the myeloid lineage and in lymphocytes. The ultimate diagnostic test is to look for a mutated LYST gene. Most patients develop an accelerated phase of the disease with deposition of lymphohistiocytes in the liver, spleen, lymph nodes and bone marrow, resulting in hepatosplenomegaly, bone marrow infiltration and haemophagocytosis. Peripheral blood neutropenia becomes more profound as anaemia and thrombocytopenia develop. Most patients succumb before the age of 10 years. Four patients with CHS are described, one of whom is a long-term survivor after successful allogeneic bone marrow transplantation, two succumbed during the accelerated phase and one is living with a chronic form of the disease. Allogeneic bone marrow transplantation from an HLA-matched sibling is the therapy of choice and should be performed early. If there is no matched family donor, an unrelated donor or a placental blood graft is a good alternative. The clinical picture of CHS is heterogeneous and therapeutic decisions need to be made on an individual basis.

Chediak-Higashi syndrome: four cases from Northern Finland

Chediak-Higashi syndrome (CHS) is a rare multiorgan disease entity with autosomal recessive inheritance characterized by oculocutaneous albinism, bleeding tendency, recurrent bacterial infections and various neurological symptoms. Intracellular vesicle formation is deficient, resulting in giant granules in many cells, e.g. giant melanosomes in the melanocytes. Diagnosis has been based on morphological examination of peripheral blood and bone marrow, with giant granules seen in cells of the myeloid lineage and in lymphocytes. The ultimate diagnostic test is to look for a mutated LYST gene. Most patients develop an accelerated phase of the disease with deposition of lymphohistiocytes in the liver, spleen, lymph nodes and bone marrow, resulting in hepatosplenomegaly, bone marrow infiltration and haemophagocytosis. Peripheral blood neutropenia becomes more profound as anaemia and thrombocytopenia develop. Most patients succumb before the age of 10 years. Four patients with CHS are described, one of whom is a long-term survivor after successful allogeneic bone marrow transplantation, two succumbed during the accelerated phase and one is living with a chronic form of the disease. Conclusion: Allogeneic bone marrow transplantation from an HLA-matched sibling is the therapy of choice and should be performed early. If there is no matched family donor, an unrelated donor or a placental blood graft is a good alternative. The clinical picture of CHS is heterogeneous and therapeutic decisions need to be made on an individual basis.

The Rat Lysosomal Trafficking Regulator(Lyst) Gene is Mapped on the Telomeric Region of Chromosome 17.

The Rat Lysosomal Trafficking Regulator(Lyst) Gene is Mapped on the Telomeric Region of Chromosome 17.

A New Beige Mutant Rat ACI/N-Lystbg-Kyo.

A new beige-like coat color mutant was identified in the ACI/N rat colony. Other features characteristic of beige mutants, such as giant granule cells in various tissues, and prolonged bleeding time were also observed. The genetic complementation test, mating beige-like mutant with the authentic beige mutant rat, DA/Ham-Lystbg, revealed that the mutant gene is allelic to Lystbg. The new beige mutant allele was denoted Lystbg-Kyo. Molecular genetic analysis revealed deletion of exons 28, 29, and 30 of the Lyst gene owing to recombination between L1 elements in the mutant rats. Although the deletion was similar to that identified in DA/Ham-Lystbg rats, the putative deletion break points in L1 elements were different in the two strains. Further characterization of the ACI/N-Lystbg-Kyo rats should make it useful as an animal model for human Chediak-Higashi syndrome.