Hermansky-Pudlak syndrome ..., types 1, 2, 3, 4, 5, 6, 7, 8, 9 (Hermansky-Pudlak syndrome, types 1, 2, 3, 4, 5, 6, 7, 8, 9 ) - Genes HPS1, AP3B1, HPS3, HPS4, HPS5, HPS6, DTNBP1, BLOC1S3 and BLOC1S6.
The Hermansky-Pudlak syndrome is a disease characterized by Oculocutaneous albinism, which causes abnormal skin pigmentation, hair and eyes. People with this disorder have a risk, above average, skin cancers and skin damage caused by prolonged sun exposure.
This disease leads to vision - related problems such as decreased pigmentation of the iris and the retina, decreased vision, nystagmus and photophobia. Usually in Hermansky-Pudlak syndrome, these vision problems remain stable after early childhood. People with Hermansky-Pudlak syndrome also have blood clotting problems causing bruising and prolonged bleeding. In addition, some people develop pulmonary fibrosis. In general, symptoms of pulmonary fibrosis appear about thirty years old and worsen quickly. Often, these individuals do not survive beyond ten years after manifesting respiratory problems. Other less common features Hermansky-Pudlak syndrome of include granulomatous colitis and renal failure.
They have differentiated nine types of Hermansky-Pudlak, which can be distinguished by their signs and symptoms and their causes genetic syndrome. Types 1 and 4 are the most serious forms of the disease. Types 1, 2 and 4 are the only types associated with pulmonary fibrosis. For its part, individuals with type 3, 5 or 6 have milder symptoms. Little is known about the signs, symptoms and severity of the types 7, 8 and 9.
This disease is due to mutations in HPS1, AP3B1, HPS3, HPS4, HPS5, HPS6, DTNBP1, BLOC1S3 and BLOC1S6 genes. Mutations in the gene are responsible HPS1 approximately 75% of cases of Hermansky-Pudlak syndrome of in Puerto Rico, while in other locations, mutations in this gene representing about 45% of all cases. Mutations in the gene HPS3 account for about 25% of the affected people of Puerto Rico and about 20% of those affected in other areas. Each of the other genes associated with Hermansky-Pudlak syndrome represent a small percentage of cases of this disease. In some people with Hermansky-Pudlak syndrome, the genetic cause of the disease is unknown.
These genes encode proteins used to constitute four different protein complexes. These protein complexes play a role in shaping and traffic - related organelle lysosome (LROS). LROS have been identified in melanocytes, platelets and lung cells. Mutations in genes associated with Hermansky-Pudlak syndrome inhibit formation LROS or impair functioning of these cellular structures. In general, mutations in genes involving the same complex proteins cause similar signs and symptoms. Individuals with this syndrome have oculocutaneous albinism because LROS within melanocytes can not produce and distribute melanin. Meanwhile, bleeding problems are due to the absence of LROS inside platelets, which affects the ability of platelets to adhere together and form a blood clot. Mutations in some genes that lead to Hermansky-Pudlak syndrome of also affect the normal operation of LROS in lung cells, leading to pulmonary fibrosis.
The HPS1 gene, located on the long arm of chromosome 10 (10q23.1-q23.3), encodes a protein forming part of a complex organelle biogenesis related lysosomes 3 (BLOC-3) complex called. This complex plays a role in the formation of a group of cell structures called organelles related to the lysosome (LROS). Within melanocytes, the melanosomes produce and distribute LROS called melanin. A different type of LRO is found in platelets. These LROS, called dense granules release chemical signals that cause platelets to adhere together and form a blood clot. The LROS also found in other specialized cells, including certain cells in the lungs. They have identified at least 31 mutations in the HPS1 gene that lead to type 1. People with this form of the disease usually have Oculocutaneous albinism, characterized by clear skin, hair and eye color, and poor vision. They may also have bleeding problems and pulmonary fibrosis. Mutations in the gene HPS1 impair the normal functioning of BLOC-3, which alters the size, structure and function of LROS in cells throughout the body. The most common mutation leads a duplication of genetic material within the HPS1 gene. Specifically, this mutation results in an extra set of 16 nucleotides within the gene (1470_1486dup16). Because melanosomes not distributed correctly abnormal melanin, people with Hermansky-Pudlak syndrome have an unusual coloration of the skin, hair and eyes. In addition, the absence of dense granules in platelets leads to bleeding problems in affected individuals.
The AP3B1 gene, located on the long arm of chromosome 5 (5q14.1), encoding a protein may play a role in the organelle biogenesis associated with melanosomes, platelet dense granules and lysosomes. The encoded protein is part heterotetrameric protein complex AP-3 interacting protein clathrin. Mutations in the gene AP3B1, give rise to Hermansky-Pudlak type 2 (HPS2) syndrome, characterized by oculocutaneous albinism, bleeding and lysosomal storage defects. Mutations in this gene, leading to defects of various cytoplasmic organelles including melanosomes, platelet dense granules and lysosomes. HPS2 differs from other forms of HPS including immunodeficiency phenotype and HPS2 patients have increased susceptibility to infections.
The HPS3 gene, located on the long arm of chromosome 3 (3q24), encodes a protein forming part of a complex organelle biogenesis related lysosomes 2 (BLOC-2) complex called. This complex plays a role in the formation of lysosome - related organelles (LROS). In particular, BLOC-2 controls the handling and transport of proteins in LROS during formation. Within melanocytes, the melanosomes produce and distribute LROS called melanin. A different type of LRO is found in platelets. These LROS, called dense granules release chemical signals that cause platelets to adhere together and form a blood clot. They have identified at least 7 HPS3 mutations in the gene responsible for Hermansky-Pudlak syndrome type 3. People usually have Oculocutaneous albinism and poor vision. They may also have bleeding problems. Mutations in the gene HPS3 impair the normal functioning of BLOC-2, which alters the size, structure and function LROS in cells throughout the body. A common mutation is a deletion of genetic material in gene HPS3. This deletion includes approximately 3,900 nucleotides (339_4260del3904). This mutation inhibits protein coding any HPS3. Another mutation, termed a splice site mutation alters the protein coding. This mutation (1163 + 1G> A), it leads to an abnormally short protein.
The HPS4 gene, located between the centromere and the long arm of chromosome 22 (22cen-q12.3), encodes a protein component BLOC. This complex plays a role in the formation of lysosome - related organelles (LROS). Mutations in the gene HPS4, leading to type 4 Hermansky-Pudlak syndrome of characterized oculocutaneous albinism, bleeding and lysosomal storage defects. This syndrome results from defects of various cytoplasmic organelles including melanosomes, platelet dense granules and lysosomes.
The HPS5 gene, located on the short arm of chromosome 11 (11p14), encoding a protein may play a role in the organelle biogenesis associated with melanosomes, platelet dense granules and lysosomes. This protein interacts with the protein encoded by the gene HPS6 and can interact with the cytoplasmic domain of integrin alpha-3. Mutations in the gene are associated HPS5 with Hermansky-Pudlak syndrome type 5 (HPS5), characterized by oculocutaneous albinism, bleeding and lysosomal storage defects. This syndrome is due to defects of various cytoplasmic organelles including melanosomes, platelet dense granules and lysosomes.
The HPS6 gene, located on the long arm of chromosome 10 (10q24.32), encodes a protein which may play a role in the organelle biogenesis associated with melanosomes, platelet dense granules and lysosomes. This protein interacts with the protein encoded by the gene HPS5. Mutations in this gene are associated with Hermansky-Pudlak syndrome type 6, characterized oculocutaneous albinism, bleeding and lysosomal storage defects. This syndrome is due to defects of various cytoplasmic organelles including melanosomes, platelet dense granules and lysosomes.
The DTNBP1 gene, located on the short arm of chromosome 6 (6p22.3), encodes a protein which may play a role in the organelle biogenesis associated with melanosomes, platelet dense granules and lysosomes. A similar protein in the mouse is a component of a complex of proteins called complex organelles related lysosomal biogenesis 1 (BLOC-1), and binds to the protein complex components associated with dystrophin (DPC). Mutations in this gene are associated with Hermansky-Pudlak syndrome type 7, characterized oculocutaneous albinism, bleeding and lysosomal storage defects. This syndrome is due to defects of various cytoplasmic organelles including melanosomes, platelet dense granules and lysosomes. Defects in the gene DTNBP1 are associated with susceptibility to schizophrenia.
The BLOC1S3 gene, located on the long arm of chromosome 19 (19q13.32), encodes a protein which is a component of a complex of proteins called complex organelles related lysosomal biogenesis 1 (BLOC-1). Mutations in this gene lead to Hermansky-Pudlak type of eight syndrome characterized by oculocutaneous albinism, bleeding and lysosomal storage defects. This syndrome is due to defects of various cytoplasmic organelles including melanosomes, platelet dense granules and lysosomes.
The BLOC1S6 gene, located on the long arm of chromosome 15 (15q21.1), encodes a protein that is a component of a complex of proteins called complex organelles related lysosomal biogenesis 1 (BLOC-1). BLOC-1 complex in association with SNARE proteins also participate in the extension of neurons. It may play a role in intracellular vesicle trafficking, particularly in the coupling process and vesicle fusion. Mutations in this gene lead to Hermansky-Pudlak type of syndrome 9, characterized oculocutaneous albinism, bleeding and lysosomal storage defects. This syndrome is due to defects of various cytoplasmic organelles including melanosomes, platelet dense granules and lysosomes.
This disease is inherited in an autosomal recessive pattern, that is, both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.
Tests in IVAMI: in IVAMI perform the detection of mutations associated with Hermansky-Pudlak syndrome, by complete PCR amplification of exons delos HPS1, AP3B1, HPS3, HPS4, HPS5, HPS6, DTNBP1, BLOC1S3 genes, and BLOC1S6 respectively, and subsequent sequencing.
Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).