Current
Executive Editor: Sandra L. Hofmann
Pycnodysostosis: Role and Regulation of
Cathepsin K in Osteoclast Function and Human Disease Pp.407-421
Gabriela
Motyckova and David E. Fisher
Neuronal Ceroid Lipofuscinoses Caused by
Defects in Soluble Lysosomal Enzymes (CLN1 and CLN2) Pp.423-437
Sandra
L. Hofmann, Armita Atashband, Steve K. Cho,Amit K. Das, Praveena Gupta and
Jui-Yun Lu
Mutated Genes in Juvenile and Variant Late
Infantile Neuronal Ceroid Lipofuscinoses Encode Lysosomal Proteins Pp.439-444
Jouni
Vesa and Leena Peltonen
The Molecular Basis of Mucolipidosis Type IV Pp.445-450
Susan
A. Slaugenhaupt
Disorders of Vesicles of Lysosomal
Lineage:The Hermansky-Pudlak Syndromes Pp.451-467
Marjan
Huizing and William A. Gahl
Chediak-Higashi Syndrome: a Clinical and
Molecular View of a Rare Lysosomal Storage Disorder Pp.469-477
Diane
McVey Ward, Shelly L. Shiflett and Jerry Kaplan
Albinism and Immunity: What’s the Link? Pp.479-483
Gillian
M. Griffiths
The Niemann-Pick C Proteins and Trafficking
of Choles-terol Through the Late Endosomal/Lysosomal System Pp.485-505
William
S. Garver and Randall A. Heidenreich
[Back to top] Pycnodysostosis: Role and Regulation of
Cathepsin K in Osteoclast Function and Human Disease
Gabriela
Motyckova and David E. Fisher
Patients with
pycnodysostosis, a rare skeletal dysplasia, present with bone abnormalities
such as short stature, acroosteolysis of distal phalanges, and skull
deformities. The disease is caused
by a deficiency of the cysteine protease cathepsin K which is responsible for
degradation of collagen type I and other bone proteins. Osteoclasts, bone cells
of hematopoietic origin responsible for bone mineral as well as protein matrix
degradation, are dysfunctional in patients with pycnodysostosis due to
mutations in the cathepsin K gene. Cathepsin K deficient osteoclasts can
demineralize bone but cannot degrade the protein matrix. Mutations in the
cathepsin K gene disrupting wild type cathepsin K activity have been described
in patients with pycnodysostosis. Animal models of cathepsin K deficiency have
been created and provide a valuable tool to study osteoclast function and
treatment for cathepsin K deficiency. Understanding the regulation and role of
cathepsin K in osteoclast function is important for designing future therapies
for pycnodysostosis. Cathepsin K inhibitors will be useful in pathological
processes involving excess osteoclast activation and bone resorption such as
osteoporosis, bone metastasis and multiple myeloma. This review will discuss the bone remodeling cycle, the
human disease pycnodysostosis caused by cathepsin K deficiency and cathepsin K
activity and regulation.
[Back to top] Neuronal Ceroid Lipofuscinoses Caused by
Defects in Soluble Lysosomal Enzymes (CLN1 and CLN2)
Sandra
L. Hofmann, Armita Atashband, Steve K. Cho,Amit K. Das, Praveena Gupta and
Jui-Yun Lu
Infantile and
classical late infantile neuronal ceroid lipofuscinoses (NCL) are two recent
additions to the expanding spectrum of lysosomal storage disorders caused by
deficiencies in lysosomal hydrolases. They are latecomers to the lysosomal
storage disorders, probably because of the heterogeneous nature of the storage
material, which precluded meaningful biochemical analysis.Infantile NCL is
caused by deficiency in palmitoyl-protein thioesterase, an enzyme that
hydrolyzes fatty acids from cysteine residues in lipid-modified proteins.
Classical late-infantile NCL is caused by a deficiency in tripeptidyl amino
peptidase-I, a lysosomal peptidase that removes three amino acids from the free
amino terminus of peptides or small proteins. Late-onset forms of these
disorders have been described. The clinical, biochemical, and molecular genetic
aspects of these two latest lysosomal storage disorders are discussed in this
review. In addition, approaches to treatment and future directions for research
are examined.
[Back to top] Mutated Genes in Juvenile and Variant Late
Infantile Neuronal Ceroid Lipofuscinoses Encode Lysosomal Proteins
Jouni
Vesa and Leena Peltonen
Positional cloning
efforts of genes mutated in Batten disease and in the Finnish type of variant
late infantile neuronal ceroid lipofuscinosis resulted in the identification of
two novel genes, CLN3 and CLN5, and corresponding gene products that proved to
be residents of lysosomes.Although the clinical phenotype of these NCL subtypes
differs in the age of onset, average life span and EEG findings, the major
component of material accumulating in patients’ lysosomes is subunit c of
mitochondrial ATPase in both these diseases. The CLN3 and CLN5 genes show
ubiquitous expression patterns and are targeted to lysosomes in vitro, but the
observed synaptosomal localization of the CLN3 protein in neurons would suggest
some cell specificity in targeting and function of these proteins. So far, 31
different mutations of the CLN3 gene have been described in Batten patients,
with one deletion of 1.02 kb accounting for 75% of disease alleles worldwide.
Four CLN5 mutations are known, with one premature stop representing the major
founder mutation in the isolated Finnish population. Functional studies of the
yeast homolog of CLN3 and increased pH in patients’ lysosomes would suggest an
involvement of this protein in lysosomal pH homeostasis. Knock-out mouse models
for CLN3 have been produced and the histopathology bears a close resemblance to
human counterparts with characteristic lysosomal accumulations. Both CLN3 and
CLN5 mouse models will provide experimental tools to resolve the pathological
cascade in these neurodegenerative diseases.
[Back to top] The Molecular Basis of Mucolipidosis Type IV
Susan
A. Slaugenhaupt
Mucolipidosis Type
IV (MLIV) is a lysosomal storage disorder that is characterized by severe
neurologic and ophthalmologic abnormalities. It is a progressive disease that
usually presents during the first year of life with mental retardation, corneal
opacities, and delayed motor milestones. First described in 1974, MLIV is a
rare autosomal recessive disease and the majority of patients diagnosed to date
are of Ashkenazi Jewish descent. MLIV was originally classified as a lysosomal
storage disorder due to the abnormal accumulation of mucopolysaccharides and
lipids. Extensive studies in MLIV cells, however, have shown that the abnormal
storage is due to a defect in the late endocytic pathway. Positional cloning
led to the recent discovery of a novel gene on human chromosome 19, MCOLN1,
that is mutated in MLIV. To date 14 independent mutations have been reported in
MCOLN1,with two mutations accounting for 95% of the Ashkenazi Jewish MLIV
alleles. The identification of the MLIV gene has led to a simple tool for
definitive diagnosis and will permit carrier screening in the Ashkenazi Jewish
population. MCOLN1 is a new member of the transient receptor potential (TRP)
cation channel gene family. The protein encoded by MCOLN1, mucolipin-1, has six
predicted transmembrane domains and a putative channel pore. The identification
of mutations in MCOLN1 represents the first example of a neurological disease
caused by a TRP-related channel. While the function of mucolipin-1 is currently
unknown, homology to the TRP superfamily and the recent description of the C.
elegans mucolipin-1 homolog allow us to begin to speculate about the role of
mucolipin-1 in diverse cellular processes.
[Back to top] Disorders of Vesicles of Lysosomal
Lineage:The Hermansky-Pudlak Syndromes
Marjan Huizing and William A. Gahl
Hermansky-Pudlak
syndrome (HPS) has evolved into a group of genetically distinct disorders
characterized by oculocutaneous albinism, a storage pool deficiency, and
impaired formation or trafficking of intracellular vesicles. HPS-1 results from
mutations in the HPS1 gene and affects approximately 400 individuals in
northwest Puerto Rico due to a 16-bp duplication in exon 15. Another 13
mutations have been reported in non-Puerto Ricans. HPS1 codes for a 79.3 kDa
cytoplasmic protein of unknown function. HPS-1 patients typically develop fatal
pulmonary fibrosis in their fourth decade. HPS-2 is caused by mutations in
ADTB3A, which codes for the b3A subunit of the adaptor protein-3 complex, AP3.
This coat protein complex has been localized to the TGN as well as to a
peripheral endosomal compartment. Evidence indicates that AP3 plays a role in
the stepwise process of vesicular trafficking which leads to formation of the
melanosomal, platelet dense body and lysosomal compartments. All three known
HPS-2 patients had childhood neutropenia and infections. HPS-3 results from
mutations in HPS3 and affects central Puerto Ricans homozygous for a 3904-bp
deletion removing exon 1. At least 8 non-Puerto Rican patients have other HPS3
mutations, including an IVS5+1G->A splicing mutation in five Ashkenazi
Jewish patients. HPS3 codes for a 113.7 kDa protein of unknown function. HPS-3
manifests with mild hypopigmentation and bleeding. All types of HPS are
diagnosed by whole mount electron microscopic demonstration of absent platelet
dense bodies, and molecular diagnoses are available for the Puerto Rican HPS1
and HPS3 founder mutations. Mouse and Drosophila models provide candidates for
new genes causing HPS in humans. These genes will reveal the pathways by which
specialized vesicles of lysosomal lineage arise within cells.
[Back to top] Chediak-Higashi Syndrome: a Clinical and Molecular View of a Rare
Lysosomal Storage Disorder
Diane
McVey Ward, Shelly L. Shiflett and Jerry Kaplan
Chediak Higashi
syndrome (CHS) is a rare, autosomal recessive disorder that affects multiple
systems of the body. Patients with CHS exhibit hypopigmentation of the skin,
eyes and hair, prolonged bleeding times, easy bruisability, recurrent
infections, abnormal NK cell function and peripheral neuropathy. Morbidity
results from patients succumbing to frequent bacterial infections or to an
"accelerated phase" lymphoproliferation into the major organs of the
body. Current treatment for the disorder is bone marrow transplant, which
alleviates the immune problems and the accelerated phase, but does not inhibit
the development of neurologic disorders that grow increasingly worse with age.
There are several animal models of CHS, the beige mouse being the most
characterized. Positional cloning and YAC complementation resulted in the
identification of the Beige and CHS1/LYST genes. These genes encode a cytosolic
protein of 430,000 Da. Sequence analysis identified three conserved regions in
the protein: a HEAT repeat motif at the amino-terminus that contains several a
helices, a BEACH domain containing the amino acid sequence WIDL, and a WD40
repeat motif, which is described as a protein-protein interaction domain. The
presence of the BEACH and WD40 domains defines a family of genes that encode
extremely large proteins.
[Back to top] Albinism and Immunity: What’s the Link?
Gillian
M. Griffiths
A small number of
inherited diseases show a combination of immunological and pigmentation
defects. Chediak-Higashi, Griscellis and Hermansky-Pudlak syndromes are all
autosomal recessive diseases with these characteristics. Recent advances in
both the identification of the genes giving rise to these diseases and the cell
biology of immune cells and melanocytes have begun to reveal the molecular
links between immunodeficiencies and albinism. These studies identify key
proteins, such as Rab27a, which are critical for secretion of specialised
granules found in melanocytes and immune cells. The granules of these cells are
modified lysosomes termed “secretory lysosomes”. These studies reveal that
secretory lysosomes use specialised mechanisms of secretion, not found in other
cell types, which explains the selective defects in these diseases.
[Back to top] The Niemann-Pick C Proteins and Trafficking of Choles-terol Through the
Late Endosomal/Lysosomal System
William
S. Garver and Randall A. Heidenreich
To maintain proper
cellular function, the amount and distribution of cholesterol residing within
cellular membranes must be regulated. The principal disorder affecting
transport of cholesterol through the late endosomal/lysosomal system and
intracellular cholesterol homeostasis is Niemann- Pick type C (NPC) disease.
The genes responsible for NPC disease have been identified, and the encoded
Niemann-Pick C1 (NPC1) and Niemann-Pick C2 (HE1/NPC2) proteins are currently
the subject of intense investigation. This review provides a detailed
examination of NPC1 and HE1/NPC2 in regulating the transport of cholesterol
through the late endosomal/lysosomal system to other cellular compartments
responsible for maintaining intracellular cholesterol homeostasis, and how
defective function of these proteins may be responsible for the pathophysiology
associated with NPC disease.