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Hermansky-Pudlak syndrome, Chediak-Chigasi syndrome, and Griscelli syndrome
Published in Electra Nicolaidou, Clio Dessinioti, Andreas D. Katsambas, Hypopigmentation, 2019
Vesna Pljakoska, Silvija Duma, Andrej Petrov
Griscelli syndrome is classified into three types, depending on the gene mutation.25 Type I26 is due to MYO5A gene mutations and is manifested by hypomelanosis, associated with primary dysfunction of central nervous system. Patients with this type of GS exhibit silvery-gray sheen of their hair and light-colored skin, as well as early and severe psychomotor retardation. They typically have delayed development, intellectual disability, seizures, weak muscle tone (hypotonia), and eye and vision abnormalities. Type II27 is caused by a mutation in the RAB27A gene, and presents with hypopigmentation, combined with variable cellular immunodeficiency. Prone to recurring infections, affected individuals may develop hemophagocytic lymphohistiocytosis, which manifests by overproduction and infiltration of activated histiocytes (T lymphocytes and macrophages), which may damage various organs and tissues, occasionally with a fatal outcome. Type III28 is also characterized by hypomelanosis, but without neurological or immunological manifestations. This type may result from a mutation in melanophilin (MLPH) or the MIO5A gene.
Color of skin
Published in Dimitris Rigopoulos, Alexander C. Katoulis, Hyperpigmentation, 2017
As melanin is deposited within melanosomes, they migrate along microtubules from the cell body into dendrites in preparation for transfer to keratinocytes. Kinesin and dynein serve as molecular motors for microtubule-associated anterograde and retrograde melanosomal transport, respectively, and UVR results in augmented anterograde transport via increased kinesin and decreased dynein activity. Myosin Va, which is linked to the melanosomal RAB27A GTPase by melanophilin, captures mature melanosomes when they reach the cell periphery and attaches them to the actin cytoskeleton. After the melanosomes are transferred to keratinocytes, melanosomes are packaged in secondary lysosomes that contain acid phosphatase. Once redistributed in the keratinocytes, melanosomes are degraded by lysosomes.9
Concurrent gut transcriptome and microbiota profiling following chronic ethanol consumption in nonhuman primates
Published in Gut Microbes, 2018
Tasha Barr, Suhas Sureshchandra, Paul Ruegger, Jingfei Zhang, Wenxiu Ma, James Borneman, Kathleen Grant, Ilhem Messaoudi
The 91 DEG that were downregulated in the ileum with ethanol consumption enriched to GO processes related to steroid/lipid metabolism (Fig. 2F). Notable DEG include the signaling molecule phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type-2-gamma (PIK3C2G); transcription factors hepatocyte nuclear factor alpha 1 and 4 (HNFA1, HNFA4); and the low-density lipoprotein receptor (LDLR) and its ligand proprotein convertase subtilisin/kexin type-9 (PCSK9). Similarly, analysis using the diseases database showed enrichment to “lipid metabolism disorders” and “metabolic diseases”. Additionally, several of the 32 genes that enriched to the disease pathway “adenocarcinoma” (Fig. 2G) are associated with progression of CRC including caspase recruitment domain-containing protein (PYCARD), melanophilin (MLPH), transient receptor potential cation channel (TRPM6), and suppressor of cytokine signaling-6 (SOCS6).
Delayed diagnosis of Griscelli syndrome type 2 with compound heterozygote RAB27A variants presenting with pulmonary failure
Published in Pediatric Hematology and Oncology, 2021
Yoav H. Messinger, Tamara C. Pozos, Anne G. Griffiths, William A. Mize, Damon R. Olson, Angela R. Smith
In mature melanocytes the GTPase Rab27a protein interacts with unconventional myosin Va (MYOVA) through a linker melanophilin, and melanocytes deficient in any of these components accumulate melanosomes near the microtubule organizing center and fail to transfer melanosomes to keratinocytes resulting in albinism.6 In cytotoxic T lymphocytes and NK cells, Rab27a protein interacts with Munc13-4 protein, synaptotagmin-like proteins Slp1, Slp2a and Slp3 as part of the complex responsible for tethering of lytic granules before the excretion of these granules containing perforin and granzyme into the immunological synapse to induce apoptosis of target cells.6 The lack of target cell death results in HLH due to lymphoproliferation and a resulting cytokine storm. In platelets, Rab27a directly interacts with the Soluble N-ethylmaleimide-sensitive factor Attachment protein REceptor (SNARE) tethering factor Munc13-4, but the presence of the redundant isoform Rab27b may prevent defect in dense-granule packaging.7 Therefore compensation by Rab27b may prevent excessive bleeding in GS2. Finally, in neurons data are emerging that Rab27a is involved with exocytotic insertion of N-type calcium channels into the plasma membrane in the hippocampus,8 controls exosome secretion in the cortex and hippocampus,9 regulates myelination processes of dorsal root ganglia in Schwann cells,9 and affects the pain response of sensory neurons.10 Notably 67% of patients with RAB27A mutations had clinical neurological manifestations5 and 10 of 38 (26%) patients with neuroinflammatory disease associated with HLH had RAB27A mutations, the second highest incidence after patients with mutations in PRF1 (61%).11
Lupus manifestations in children with primary immunodeficiency diseases: Comprehensive phenotypic and genetic features and outcome
Published in Modern Rheumatology, 2021
Sulaiman M. Al-Mayouf, Hajar A. Alreefi, Tuqa A. Alsinan, Ghada AlSalmi, Abdulaziz AlRowais, Waleed Al-Herz, Anas M. Alazami, Abdullah Alsonbul, Hamoud Al-Mousa
Seven patients were identified with seven different unique immunity defects compatible with PIDs. The current age was 10.5 (range of 7–24) years and the mean age at the onset of lupus manifestations was 6.4 ± 2.5 years. The diagnosis of PIDs was made based on the molecular genetic findings in all patients. Five patients fulfilled the criteria of SLE; they had mucocutaneous manifestations, alopecia and arthritis, besides elevated ANA and ds-DNA, and antiphospholipid antibodies. First patient had purine nucleoside phosphorylase (PNP) deficiency with homozygous PNP mutation and presented with serious recurrent bacterial and viral infections [16]. She developed dysarthria, and ataxic gait and brain MRI showed white matter changes. She also subsequently developed biopsy proven membranoproliferative glomerulonephritis. Second patient had homozygous DNase II variant and presented with non-destructive, deforming arthropathy involving small joints of both hands. He had recurrent headaches and mild cognitive impairment and mild learning difficulties, and brain MRI showed white matter changes. Third patient had heterozygous PIK3CD variant and presented with chronic lung infiltration and subsequently developed bronchiectasis. Fourth patient with chronic granulomatous disease (CGD) had hemizygous L406X mutation in CYBB gene. He presented with leukocytoclastic vasculitis and renal impairment with biopsy proven chronic interstitial fibrosis and tubular atrophy. Another three patients with PIDs had few clinical features of SLE. However, they had significant ANA positivity, and three patients had elevated ds-DNA antibodies. First patient presented with oral ulcer, epilepsy, cognitive, behavioral impairment, and hypopigmentation of the skin and slivery-gray hair and malar rash, and ANA positivity, WES identified homozygous ISG15 and melanophilin (MLPH) variant. Second patient had recurrent oral ulceration and autoimmune hemolytic anemia with thrombocytopenia and high ANA. Interestingly, genetic testing showed compound heterozygous interleukin-2 receptor β chain (IL-2RB) variants. Third patient presented with erosive arthropathy and contracture of small joints of both hands. She had neurological disorder in form of optic atrophy and hyperintense lesions in supratentorial periventricular and subcortical white matter proved by brain MRI. She had missense heterozygous signal transducer and activator of transcription 1 (STAT1) variant.