Traffic 2000 1: 836–851

Munksgaard International Publishers

Toolbox

Traffic Jam: A Compendium of Human Diseases that

Affect Intracellular Transport Processes

Meir Aridora and Lisa A. Hannanb,*

a
Department of Cell Biology and Physiology, University of
Pittsburgh, School of Medicine, 3500 Terrace St, Pittsburgh
PA 15261, USA
b
Traffic Editorial Office, The Scripps Research Institute,
10550 N Torrey Pines Rd TPC 27, La Jolla, CA 92037, USA
* Corresponding authors: M. Aridor, aridor + @pitt.edu/
L.A. Hannan, traffic@scripps.edu
As sequencing of the human genome nears completion,
the genes that cause many human diseases are being
identified and functionally described. This has revealed
that many human diseases are due to defects of intracel-
lular trafficking. This ‘Toolbox’ catalogs and briefly de-
scribes these diseases.
Key words: Disease, syndrome, traffic, transport
Received and accepted for publication 21 August 2000
Eukaryotic cells have evolved to compartmentalize enzymatic
activities to specific organelles. Compartmentalization re-
quires that the cell transport macromolecules from their site
of synthesis to the appropriate specialized compartment.
Disruption of some transport events has been determined to
be the molecular basis or target for many hereditary and
autoimmune diseases. In this ‘Toolbox’ we have catalogued,
described and indicated the primary clinical manifestation for
each of these diseases. The diseases are categorized accord-
ing the transport step affected. The list is available on-line at
www.traffic.dk, and will be updated as new entries are
submitted. We invite submission of new diseases to be
included in the list to the Traffic editorial office. A better
understanding of the molecular basis that underlies all these
diseases will open the way to possible therapeutic interven-
tion and better treatments.

Endoplasmic Reticulum: The First Stop

The first compartment of the secretory pathway is the endoplasmic reticulum (ER). The proteins and lipids that are processed and
transported through the ER represent a wide variety of cargo molecules (i.e. extracellular receptors and ion channels to be expressed
on the plasma membrane, enzymes and hormones destined to be secreted from the cell, enzymes that function within organelles as
well as lipids and lipid precursors). These macromolecules are involved in a broad range of physiological processes, therefore varied
disease phenotypes develop by disruption of ER-mediated transport events.

Newly synthesized polypeptides are co-translationally inserted into the ER where they undergo folding and oligomerization (in the case
of multi-subunit protein complexes) that is assisted and carefully monitored by ER resident lectins, enzymes and chaperones. Mature,
properly folded and assembled proteins assume a transport-competent conformation and are recognized by the molecular export
machinery that mediates ER export for delivery to the Golgi. Proteins that fail to achieve functionality are identified by ER signaling receptors
and degraded to prevent their accumulation. ER signaling pathways are activated in response to misfolded proteins to induce the expression
of folding and transport machinery proteins to accommodate for the increase in transport/degradation load. In severe cases, where this
up-regulation cannot eliminate the defective cargo and prevent its accumulation, ER signaling shifts to induce cellular apoptosis, thus
eliminating the affected cell in order to preserve tissue functionality.

In this ‘Toolbox’, we have divided ER-related diseases into three groups. In the first group (cargo retention and degradation), mutated
cargo molecules that fail to achieve transport-competent conformation are eliminated by the degradation machinery. In some cases,
the affected cargo can retain partial functionality, which may be sufficient to fulfill its physiological role. However, the defective cargo
fails to engage the export machinery, is not delivered to its site of action and is routed for ER degradation. It is the loss of cargo function
that leads to disease. Lipid transport diseases represent a unique subgroup within this section and are grouped separately.

In the second group (cargo accumulation and ER stress), cargo is not efficiently degraded and begins to accumulate in the ER. The
reasons for this partial uncoupling from the degradative arm are unknown. However, under these conditions, the ER signaling initiated
culminates in apoptosis of the host cell. The disease is manifested both by damage to the cargo-producing tissue and by phenotypes
that are attributed to the loss of cargo function. (Amyloid production where partially or undegraded cargo can polymerize to form a
protease-resistant aggregate within the cell may be a specialized form of cargo accumulation.)

The third group is unique in that these diseases are not due to defects in the cargo molecules but are due to defects in the machinery
required for transport from the ER to the Golgi complex. These are the ER transport machinery diseases.

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 Human Diseases Affecting Intracellular Transport

Disease (reference) Defective Primary clinical Phenotype and cellular pathology

gene/protein manifestation

Cargo retention and degradation in the ER

Cystic fibrosis (1,2) Cystic fibrosis Lung disease Mutations in this chloride conductance channel (CFTR) lead
transmembrane to the retention and degradation of the protein in the ER.
regulator (CFTR) The disease results from loss of chloride regulation in
CFTR-expressing epithelia of secreting organs. Deletion of
Phe at position 508 in CFTR accounts for more than 70% of
all cases. Interestingly, this CFTRD F508 mutant retains
partial activity and can be stabilized for transport and surface
expression with chemical chaperones.

Hereditary a1-Antitrypsin (PiZ) Lung disease The protein, which is required for inhibition of elastase
emphysema variant activity in the lung, is retained in the ER of hepatocytes (its
(3) site of production) and is degraded. This secretion block
leads to degradation of elastin in the lungs and to the
development of emphysema.

Hereditary HFE Liver disease Mutations in this non-classical MHC1-like protein lead to its
hemochromatosis ER retention and degradation. The protein normally interacts
(4 – 8) with the transferrin receptor to regulate iron uptake and
hemostasis.

Oculocutaneous Tyrosinase Pigmentation Mutations in tyrosinase lead to its retention in the ER. The
albinism (9) defect enzyme is not delivered to its post Golgi target, the
melanosome, where normally it plays a key role in melanin
biosynthesis.

Protein C Protein C Blood disease Mutations in this coagulation factor lead to ER retention and
deficiency degradation. This block in secretion leads to deficiencies in
(10,11) coagulation.
Type I hereditary Complement C1 Immunodeficiency, Mutations that prevent ER export and lead to degradation of
angioedema inhibitor (C1-INH) skin disease the inhibitor cause deficiency in C1-INH in affected patients.
(12,13)

Fabri disease a-D-galactosidase Neurological This lysosomal storage disease results from mutations in
(14,15) disease, endocrine a-D-galactosidase leading to the production of a thermolabile
defect enzyme that is retained and degraded in the ER. Some of
these mutated enzymes can be stabilized by chemical
chaperones, to produce transport compatible, partially
functional enzyme.
Tay–Sachs Beta Neurological Tay–Sachs is another example of a lysosomal storage
(16 – 19) hexosaminidase disease, endocrine disease that arises from enzyme retention/degradation in the
defect ER due to mutations that affect folding. The mutated
enzyme is retained and degraded in the ER.

Congenital Sucrase-isomaltase Gastrointestinal Mutations lead to ER retention and therefore block the
sucrase-isomaltase disease delivery of the enzyme to the brush border membrane, its
deficiency site of action.
(20 – 22)

Crigler–Najjar UDP-glucuronosyl- Liver disease One identified mutation disrupts the hydrophobic core of the
type II (23,24) transferase signal peptide of this ER membrane enzyme that catalyzes
the glucoronidation of small lipophilic metabolites in the ER,
leading to loss of function.

Diabetes Insulin receptor Diabetes Class 2 mutations in insulin receptor impair its transport
mellitus from the ER, markedly reducing its surface expression
(25,26) leading to insulin resistance.

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Endoplasmic Reticulum: The First Stop (Continued)

Disease (reference) Defective Primary clinical Phenotype and cellular pathology
gene/protein manifestation

Laron syndrome (27) Growth hormone Developmental Mutations in the receptor lead to ER retention and
receptor defects, endocrine reduced surface expression. Lack of receptors on the
defect plasma membrane of expressing cells leads to severe
growth retardation, small gonads and genitalia, and
obesity.
Hereditary MPO Cancer, Mutations in the protein cause extended association with
m6 yelop6 ero6 xidase immunodeficiency ER chaperones, ER retention and degradation leading to
(28) increased susceptibility to infection and malignancy.

Primary Preproparathyroid Endocrine defects In one example, mutations of preproPTH in the

hypothyroidism hormone hydrophobic core of the signal peptide lead to impaired
(29,30) (preproPTH) translocation into the ER, lack of processing, secretion
block and, therefore, hormone deficiency.

Congenital Long QT Voltage gated Heart disease Mutations in HERG lead to ER retention and degradation.
syndrome (31,32) potassium channel Loss of channel gating activity leads to delayed cardiac
(HERG) repolarization, prolonged electrocardiac QT intervals, the
development of ventricular arythmias and sudden death.

Tyroxine binding Tyroxine binding Endocrine defects TBG is the principal transport protein for thyroid hormone
globulin deficiency globulin (TBG) in the circulation. Mutations in TBG lead to retention in
(33,34) the ER and block of TBG secretion.

Lipid transport diseases related to the ER

Familial Low-density Vascular disease Variety of mutations in the LDL receptor lead to ER
hypercholesterolemia lipoprotein (LDL) retention and degradation, thus preventing cell surface
(35 – 40,96) receptor expression. This results in defective LDL transport and
increased serum levels of cholesterol.

Familial Lipoprotein lipase Vascular disease LPL is secreted from muscle and fat cells and is
chylomicronemia (LPL) transported to capillary endothelium where it catalyzes
(41,42) hydrolysis of triglycerides within chylomicrons and VLDL
particles. Some mutations in the protein lead to prolonged
ER retention and secretion block.

Abeta-lipoproteinema Microsomal Vascular disease Mutations in MTP, a protein which associates with the
(43 – 48) triglyceride ER-folding machinery and is involved in the co-translational
transfer protein lipid packaging of apolipoprotein B (ApoB), lead to loss of
(MTP) export of ApoB from the ER and, therefore, the virtual
absence of ApoB-containing lipoproteins in the plasma.

Low plasma Apolipoprotein a Vascular disease, In ‘null’ alleles, which produce no detectable plasma Lp(a),
lipoprotein a levels (apo(a)) liver disease Apo(a) proteins were retained in the endoplasmic
(49) reticulum. Low plasma lipoprotein a levels are associated
with vascular and liver diseases.

Cargo accumulation leading to ER signaling and stress

Hereditary a1-Antitrypsin (PiZ) Lung disease, liver A subset of patients display accumulation and inefficient
emphysema with variant disease degradation of mutated a1-Antitrypsin (PiZ), which leads to
liver injury (3) loss of lung function (emphysema) and to injury of the
producing tissue, the liver, through chronic activation of
ER stress.

Congenital Thyroglobulin Endocrine disease, Mutated thyroglobulin (Tg) accumulates in the ER leading
hypothyroidism developmental to ER signaling and a marked expansion of the
(50,51) defect compartment. In a subset of patients, the observed
increase in biosynthetic activity of the ER, while leading to
the development of goiter, can achieve comparable levels

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 Human Diseases Affecting Intracellular Transport

Endoplasmic Reticulum: The First Stop (Continued)

Disease (reference) Defective Primary clinical Phenotype and cellular pathology
gene/protein manifestation

of thyroglobulin in circulation. This may be the

consequence of a minor fraction of Tg that leaves the ER,
and the increase in size of the compartment which
accounts for the ‘normalized’ hormone secretion.
Osteogenesis Type I Skeletal deformity Mutations disrupt folding and assembly of pro-collagen
imperfecta (OI) pro-collagen and delay formation of disulfide-linked tri-mers composed
(52 – 54) of two pro-a-1 and one pro-a-2 chains, which are exported
from the ER. Collagen contains a characteristic triple
helical structure, which is made of Gly-X-Y repeats (where
X is often proline and Y is often hydroxyproline).
Mutations, which are often found in these repeats, disrupt
the triple helical domain, and the severity of the disease
may be correlated with the location of the mutations along
the pro-a chains. The severity of the diseases ranges from
death in utero to mild bone fragility. In some mutants, the
subunits can associate slowly and exit the ER to alleviate
the possible chronic stress response. Indeed, null alleles,
which do not lead to the induction of ER stress, cause a
relatively mild disease.
Hereditary Fibrinogen Liver disease ER retention in hepatocytes may lead to stress signaling,
hypofibrinogenemia ER dilation and tissue injury, i.e. liver cirrhosis.
(55 – 58)
Alpha-1-antichymo- ACT Lung disease, liver Some mutants are retained in the ER of the liver, where
trypsin (ACT) disease the enzyme is produced. This leads to defects of the liver
deficiency (57,59) and also of the lung where it is required for proper lung
function.
Nephrogenic diabetes Water channel Diabetes Point mutations found in AQP2 lead to ER retention.
insipidus (60,61) aquaporin-2 Interestingly, some mutated proteins are exported from
(AQP2) the ER in the presence of chemical chaperones such as
glycerol and are redistributed to normal
membrane/endosome localization. Water permeability
measurements indicated that the water channel is
functionally active under these conditions.
Neurohypophyseal Vasopressin Diabetes One interesting (although rare) mutation produces a
diabetes insipidus precursor protein protein containing a truncated signal sequence that is
(62 – 65) prepro-vasopressin- functional for targeting and translocation into the ER but is
neurophysin II not cleaved by signal peptidase. The resulting mutant
precursor aggregates and is retained in the endoplasmic
reticulum. Accumulation in the ER leads to ER stress and
cellular toxicity.
Charcot–Marie– Peripheral myelin Neurological Mutant protein accumulates in the endoplasmic reticulum.
Tooth syndrome protein 22 disease, Signaling from the ER may contribute to abnormal growth
(66 – 70) (PMP22) degenerative and differentiation.
muscle disease
Pelizaeus– Proteolipid protein Neurological Mutations accumulate PLP gene products in ER, leading
Merzbacher disease (PLP) gene disease to ER stress signaling and oligodendrocyte death by
(71 – 73) apoptosis.
Alzheimer disease Presenilin Neurological Presenilins which are largely localized to the ER are
(74 – 76) disease involved in the proteolytic processing of receptors that
signal through R6 egulated I6 ntramembrane P6 roteolysis
mechanism (RIP). Mutations in presenilins were identified
as a cause for early onset of Alzheimers disease.

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Endoplasmic Reticulum: The First Stop (Continued)

Disease (reference) Defective Primary clinical Phenotype and cellular pathology
gene/protein manifestation

Mutated presenilins can lead to generation of amyloids by

supporting the cleavage of the A6 myloid P6 recursor P6 rotein
(APP) and generation of the beta 1-42 amyloid peptide.
Interestingly, presenilins are involved in the signaling
cascade, which reports ER stress (possibly through RIP
mechanisms). Whether amyloid peptide formation is a
bi-product of ER stress or the cause for the observed
degeneration in the neuronal host cells remains to be
determined.
von Willebrand von Willebrand Blood disease Some patients with this bleeding disorder have mutations
disease type IIA factor (vWF) in vWF that result in its retention in the ER.
(77,78)

ER transport machinery diseases

Combined factors V ERGIC-53/p58 Blood disease This mannose-binding lectin cycles in the early secretory
and VIII deficiency pathway and serves as a cargo receptor for incorporation
(79) of a specific cargo protein into COPII vesicles. Lack of
ERGIC53, due to mis-sense mutations, leads to a
secretion block of coagulation factors V and VIII and
development of the bleeding disorder.

Spondylo-epiphyseal SEDL (sedlin) Skeletal defect Sedlin is homologous to yeast p20 of the Transport
dysplasia tarda (80) Protein Particle (TRAPP) which is required for ER-Golgi
transport. This defect may result in defective collagen
transport which causes skeletal abnormalities.

Golgi, TGN and Endocytic Trafficking: Moving on Through

Following ER export, cargo is delivered to the Golgi. The Golgi complex is a network of stacked membrane cisternae. Proteins and lipids
are modified within the cisternae and delivered to the trans -Golgi network (TGN) where they are sorted for delivery to their site of action
(i.e. lysosomes, secretory granules, plasma membrane and endocytic system). The sorting determinants for many compartments have
not been identified. However, in some cases (such as addition of mannose-6-phosphate) the post-translational modifications that occur
in the Golgi are known to tag the molecule for delivery to specific destinations. Extracellular receptors are delivered from the TGN to
the plasma membrane where they interact with the external environment and mediate uptake of extracellular molecules such as proteins
(growth factors, antigens), nutrients and pathogenic organisms.

Many of the diseases that affect the Golgi, TGN and endocytic systems are due to defects in the machinery required for intracellular
transport. Some of the components that are known to cause human hereditary diseases include an enzyme required for post-translational
modification of proteins, defects in coat proteins, defects that interfere with association with coat proteins, and disruption of the structure
of the Golgi or endosomal compartment. Antigen presentation and lipid trafficking are specialized functions of the ER, Golgi and endocytic
trafficking system and defects in these processes are also included in this category.

Disease Defective gene or Primary clinical Phenotype and cellular pathology

protein manifestation

Choroideremia (81,82) Rab escort protein Eye disease Rep1 is component A of rab geranylgeranyl
(Rep1) transferase required for post-translational
processing of rab proteins. Rab27a selectively
lacks geranylation in choroideremia patients
resulting in a degeneration in the pigment
epithelium of the eye. Since prenylation of rab
proteins is required for their regulation of

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 Human Diseases Affecting Intracellular Transport

(Continued)
Disease Defective gene or Primary clinical Phenotype and cellular pathology
protein manifestation

intracellular trafficking events, a defect in an

enzyme in this pathway is likely to have profound
effects on intracellular trafficking events.
I cell disease (83) N-acetylglucosamine Neurological disease In this lysosomal storage disorder,
1-phosphotransferase mannose-6-phosphate is not added to lysosomal
enzymes. As a result, newly synthesized
lysosomal proteins are secreted and inefficiently
transported to lysosomes.
Batten disease CLN1-CLN 8 (8 Neurological disease Eight distinct genes are responsible for the
(neuronal c6 eroid- known alleles) lysosomal storage diseases known as Batten
l6 ipofuscinoses) (84) disease. These include: CLN1 (palmitoyl:protein
thioesterase), CLN2 (tripeptidylpeptidase 1), CLN3
(proposed to have a role in recycling of synaptic
vesicles), CLN5 (unknown function), CLN8
(cathepsin D). These defects cause a lysosomal
accumulation of an autofluorescent material that
is resistant to analysis.
Ataxia telangiectasias Ataxia telangiectasias Cancer, neurological ATM is member of the phospho-inositide
(85) mutated (ATM) disease, eye disease, 3-kinase family. ATM has also been shown to
immunedeficiency, interact with adaptin, and therefore may play a
endocrine disease role in vesicle transport.
Acute CALM Cancer CALM is a homologue of a synapse-specific
lymphoblastic leukemia clathrin assembly protein, AP180. CALM binds
or acute myeloid clathrin, and its overexpression inhibits
leukemia (86–88) endocytosis. CALM fused to the transcription
factor AF-10 is a rare but recurring mutation
associated with these two forms of leukemia.
Myeloid leukemia (89) AF1p Cancer Af1p is the human homologue of murine EPS15.
AF1p fused to the ALL1/HRX transcription factor
is associated with two forms of myeloid
leukemia.
Acute myeloid leukemia EEN Cancer EEN encodes SH3p8, the human homologue of
(90) endophilin II. Endophillin II has been shown to be
involved in endocytosis through its interaction
with dynamin and synaptojanin. A fusion of
SH3p8 with the ALL1/HRX transcription factor is
associated with some forms of myeloid
leukemias.
ADPKD-autosomal PKD1 and PKD2 Kidney disease Mutations in the polycystins disrupt
dominant polycystic (two known alleles) E-cadherin-dependent cytoarchitecture and
kidney disease (91,92) localization of proteins in the secretory route, and
interfere with basolateral trafficking in kidney
epithelia of affected patients.
Microvillus inclusion Unknown Gastrointestinal disease Presumptive defects in trafficking along the apical
disease (93) exocytic pathway in enterocytes leads to
accumulation of apical markers in subapical
vesicular structures, which include structures that
appear to be microvilli.
Tuberous sclerosis (94) Tuberin and Cancer, neurological Tuberin is thought to function as a Rab5 GTPase
hamamartin (two disease activating protein (Rab5GAP). Tuberin negatively
known alleles) regulates endocytosis, leading to malformations

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Aridor and Hannan

(Continued)
Disease Defective gene or Primary clinical Phenotype and cellular pathology
protein manifestation

and tumors in the central nervous system as well

as cutaneous lesions. Hamamartin and tuberin
form a complex, and defects in either protein
result in identical phenotypes. Therefore,
hamamartin is thought to also play a role in
vesicular transport

O6 culoc6 erebro-r6 enal Ocrl-1 Eye disease, kidney OCRL1 is homologous to phosphatidylinositol
syndrome of L6 owe (95) disease, neurological 4,5-bisphosphatase. PtdIns(4,5)P2 5-phosphate
disease (PIP2) has been implicated in regulation of Golgi
function through activation of phospholipase D
and regulation of actin assembly. Disruption of
Golgi function is thought to be the cause of the
developmental defects of the lens as well as
abnormalities of renal and neurological tissues,
which are characteristic of Lowe’s disease.
Cushings disease (97) Unknown Cancer Morphological examination of tumor (adenoma)
cells from Cushing’s disease patients shows a
disruption of the Golgi and secretory granules.
Amyotrophic lateral Unknown Neurological disease Motor neurons from patients with amyotrophic
sclerosis (98) lateral sclerosis show a fragmentation of the
Golgi apparatus.
Diseases affecting antigen presentation: a specialized function of the secretory and endocytic pathways
Myelodysplastic Unknown Immunodeficiency Dendritic cells from patients with myelodysplastic
syndrome (99) syndrome demonstrate defective antigen uptake
and presentation, presumably due to reduced
surface levels of MHC class II and a reduction in
the rate of fluid phase endocytosis.
Bare lymphocyte RFX-B, CIITA, TAP1, Immunodeficiency Lymphocytes from patients with bare lymphocyte
syndrome (100–103) TAP2 syndrome show no surface expression of either
(four known alleles) MHC class I (defects in TAP1 and TAP2), or
MHC class II (defects in CIITA and RFX-B), and
therefore defective antigen presentation.
Diseases in lipid transport
Niemann Pick C (104) NPC1 Neurological disease NPC1 is a sterol sensing protein required for
transport of cholesteryl ester (and potentially fluid
phase constituents) from the late
endosome/lysosome to other organelles. Defects
result in an accumulation of lipid in lysosomes.
Tangier disease ATP binding cassette Neurological disease, ABC1 transports lipid-free high-density lipoprotein
(105,106) transporter 1 (ABC1) liver disease and mediates export of cholesterol and
phospholipids. Mutations in this protein cause
morphological changes in the Golgi and
lysosomes of mononuclear phagocytes.
Familial intrahepatic MDR3 Liver disease The MDR3 gene product is an ABC transporter
cholestasis [reviewed in that has been shown to transport
(107)] phosphatidylcholine out of the cell across the
canalicular membrane in hepatic cells.
X-linked ALD Neurological disease ALD encodes one subunit of the peroxisomal
adreno-leukodystrophy membrane ABC transporter responsible for
[reviewed in (107)] transport of fatty acids into peroxisomes.

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(Continued)
Disease Defective gene or Primary clinical Phenotype and cellular pathology
protein manifestation

Scott syndrome Scramblase Blood disease Scott syndrome is a rare bleeding disorder
[reviewed in (107)] caused by a platelet coagulant defect that results
from mutations in scramblase. Scramblase is
responsible for the bidirectional transport of
phospholipids (independently of the head group)
across the plasma membrane.

The Lysosomes: A Final Destination

Lysosomes are the major site of intracellular catabolic processes. There are many lysosomal storage disorders that are the result of
defects in specific catabolic enzymes. They result in incomplete degradation of macromolecules, which in turn results in the
accumulation of the metabolic intermediate in lysosomes. It is not clear if these should be considered trafficking defects, and they
have been reviewed in detail elsewhere (108). Therefore, they have not been included on this list. In contrast, it has been shown
recently in the case of some of the sphingolipidosis class of lysosomal storage diseases, that the accumulation of the primary catabolic
intermediate results in a change in the lipid environment/raft composition, and results in altered trafficking of other macromolecules
[reviewed in (109)].
There are also several diseases that apparently affect the transport machinery for lysosomes (i.e. Hermansky – Pudlak syndrome,
Chediak – Higashi syndrome and Griscelli’s disease). These all result in defective lysosome and lysosome-related organelles (i.e.
melanosomes, platelet storage granules and cytolytic granules). As a result, patients with these diseases are characterized by a
combination of partial albinism, bleeding disorders and immunodeficiency.

Disease Defective gene/protein Primary clinical Phenotype and cellular pathology

manifestation

Lysosomal storage diseases

Sphingolipidosis [reviewed b-D-galactosidase, Neurological disease These enzymatic defects cause
in (108,109)] Gm1, b-hexosaminidase inappropriate processing of sphingolipids
gangliosidosis, late onset (a-subunit and b-subunit), that lead to the accumulation of the
GM2 gangliosidosis (variant a-D-galactosidase, acid incorrectly modified sphingolipids in the
B), Sandhoff disease sphingomyelinase lysosomes. Due to this redistribution,
(variant O), Fabry disease, other sphingolipids, cholesterol and the
Niemann Pick A and B sterol sensing protein NPC1 accumulate
in late endosomes and lysosomes. These
patients suffer severe and progressive
neurological defects.
Mucolipidosis IV [reviewed Unknown Neurological disease Sphingolipids, phospholipids and acid
in (108,109)] mucopolysaccharides accumulate in
lysosomes. Due to the redistribution of
sphingolipid, cholesterol and the sterol
sensing protein NPC1 accumulate in late
endosomes and lysosomes.
Sphingolipid activator Prosaposins Neurological disease The prosaposins are small acidic proteins
protein deficiencies required for the hydrolysis of
[reviewed in (108,109)] sphingolipids, and therefore defects
result in the accumulation of specific
sphingolipids
Diseases of lysosome biogenesis and trafficking
Hermansky–Pudlak HPS1 Pigmentation defect, HPS1p is thought to transiently associate
syndrome type 1 (HPS 1) Immunodeficiency, with the lysosomal membrane, and
(110,138) Blood disease mediate biogenesis and/or function of
lysosomes and related organelles.
Lysosomal proteins appear to be
appropriately transported and distributed.

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Aridor and Hannan
(Continued)
Disease
Hermansky–Pudlak
syndrome type 2 (HPS 2)
(111,138)
Chediak–Higashi syndrome
(112,113)
Griscelli disease with Rab27
haemophagic syndrome (114)
Danon disease (139)
The Ins and Outs of Transport: Diseases that Affect Mitochondria, Peroxisomes and Nuclear
Import
Translocation of polypeptides across membranes is an essential step in the insertion of cargo into and the assembly and function of
organelles. We have listed some defects in targeting and translocation into the ER above. Below are additional diseases that arise from
defects in translocation into other organelles in eukaryotic cells. These highlight the role of sorting signals in recognition and targeting
of proteins within compartments.
Disease
Zellweger syndrome
(cerebro-hepato-renal
syndrome) [(115),
reviewed in (116)]
844
Defective gene/protein Primary clinical Phenotype and cellular pathology
manifestation
Hermansky–Pudlak patients are
characterized by hypopigmentation due to
defective melanosomes, bleeding disorders
due the platelet storage pool defects and
restrictive lung disease.
b3A subunit of AP-3 Pigmentation defect, Mutations in the AP-3 coat protein
adaptor immunodeficiency, complex results in mislocalization of
blood disease several lysosomal proteins to the plasma
membrane. Although the primary defect in
HPS2 patients is different from HPS1,
these patients are similarly affected.
LYST Pigmentation defect, Lysosome and lysosome-related organelle
immunodeficiency function is disrupted due to mutations in
the 429-kDa LYST protein, resulting in
immune insufficiency and albinism. The
mechanism by which LYST regulates
lysosome function is unknown, although
subdomains of LYST show homology to
other proteins involved in intracellular
trafficking.
Pigmentation defect, Griscelli’s disease appears to be the result
immunodeficiency of mutations in either of two neighboring
genes of chromosome locus 15q21. The
first is Rab27 and the second is myosin5a.
While mutations in either gene results in
partial albinism, only those with mutations
in Rab27 show uncontrolled T-lymphocyte
activation, indicating that Rab27 may be
required for the exocytosis of cytolytic
granules.
Lamp 2 Heart disease, Lamp 2 may be required for the
neurological disease, conversion of early autophagic vacuoles to
muscle disease vacuoles, possibly in the process of
autophagic vacuole fusion with
endosomes/lysosomes. Loss of Lamp 2
leads to the development of a lysosomal
glycogen storage disease with normal acid
maltase.
Defective Clinical manifestation Phenotype and cellular pathology
gene/protein
Pex1, Pex2, Pex5, Neurological disease, Defects in these Pex proteins result in
Pex6, Pex10, Pex12 liver disease, kidney defective import of peroxisomal matrix
(total of 10 known disease proteins with the PTS1-targeting sequence.
alleles) This fatal disease results in a severe
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(Continued)
Disease Defective clinical manifestation Phenotype and cellular pathology
gene/protein

reduction in the number of peroxisomes and

Rhizomelic chondro-
dysplasia puncta
[reviewed in (116)]
Autosomal recessive
primary hyper-
oxaluria (117)
Mohr Tranebjaerg DDP1
syndrome (human deafness
dystonia syndrome) (118)
Spinal and bulbar
muscular
atrophy (119)
consequently those metabolic processes that
occur within the peroxisome.
Pex7 Skeletal defect, Patients with mutant pex7 have defective
neurological disease import of peroxisomal membrane proteins
that contain the PTS2 targeting sequence
without a concurrent reduction in the number
of peroxisomes.
Alanine/glyoxylate Kidney disease The hepatic alanine/glyoxylate amino
amino transferase transferase is normally localized to
peroxisomes, but is mistargeted to
mitochondria in patients with primary
hyperoxaluria. This results in incorrect
glyoxylate metabolism to form oxalate and
glycolate. Hyperexcretion of these acidic
compounds into the urine leads to renal
insufficiency.
Neurological disease DPP1 is the human homologue of yeast Tim
8. Tim 8 is a small intermembrane protein in
mitochondria, and delivers cargo from the
outer membrane general import pore (GIP) to
the inner membrane Tim 22 complex. The
neural degeneration caused by defects in
DPP1 leads to progressive sensoro-neural
deafness, cortical blindness and dystonia.
Androgen receptor Endocrine defect Cytoplasmic to nuclear translocation of the
mutant androgen receptor is delayed and
large aggregates of the receptor form in the
presence of androgens. Patients suffer from
androgen insensitivity and progressive
weakness and wasting of the limbs.

The Roads and Engines for Intracellular Transport: Diseases that Affect the Cytoskeleton and
Molecular Motors
In order to cover the distance between compartments more efficiently, eukaryotic cells take advantage of the cytoskeleton and the
molecular motors that move on them. These are required for intracellular movement of organelles and vesicles, as well as movement
of the whole cell. It is becoming clear that these elements not only play a role in movement of organelles but also play a role in cargo
sorting.

Defects of the cytoskeleton and molecular motors result in a variety of phenotypes that include defective motility of either the entire
cell (i.e. neuronal migration), or non-functional cilia or flagella. The phenotype of defects in cilia/flagella function range from male
infertility, deafness, increased susceptibility to respiratory diseases and altered left/right organ asymmetry. This last phenotype likely
results from the inability of a morphogen gradient to be generated by primary nodal cilia during early embryogenesis [see (120)].

Disease (reference) Defective gene or Primary clinical Phenotype and cellular pathology
protein manifestation

Primary ciliary diskenesia DNAI1 – dynein Developmental defect, Defective dynein leads to abnormal ciliar
(PCD)/Kartagener’s intermediate chain lung disease, and axonemal structure and function. Due
syndrome (121) hearing loss to the loss of function of cilia, these pa-
tients suffer from chronic middle ear, sinus

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Aridor and Hannan
(Continued)
Disease (reference)
Miller Dieker syndrome
(122)
Lissencephaly (123)
Motor neuron disease
(124)
Griscelli disease [reviewed
in (125)]
Usher’s syndrome
[reviewed in (125)]
Wiskott–Aldrich syndrome
(126)
Alzheimer’s disease (127)
Frontotemporal dementia
with Parkinsonism
(reviewed in (128))
Optiz syndrome (129)
846
Defective gene or Primary clinical Phenotype and cellular pathology
protein manifestation
and lung disease. Interestingly, PCD is also
associated with organ asymmetry, which is
likely to be the result of an inability of the
early embryo to develop a gradient of
extracellular morphogens [see (120)].
Lis1 Neurological disease, Lis 1 (homologous to Aspergillus nidulans
developmental defect NUDF) functions with the dynein complex
to regulate nuclear and cell migration.
Abnormal neuronal migration results in
severe congenital brain malformation.
Doublecortin Neurological disease Doublecortin directly binds to and stabilizes
microtubules, and has been implicated in
neuronal migration (see above).
Unknown Neurological disease Kinesin accumulates in axonal spheroids of
motor neurons, and impairs anterograde
fast axonal transport.
Myosin 5a Pigmentation defects, In patients with defective myosin 5, lyso-
neurological disease, some-related organelles fail to transport to
immunodeficiency the appropriate location. This results in al-
binism, neurological and immunological de-
fects.
Myosin 7 Hearing loss Myosin 7 is thought to be required for
transport from the Golgi to specific polar-
ized regions of the cell. Deafness associ-
ated with defects in these patients is likely
due to a loss of integrity of the hair cell
bundle in the ear.
WASP Immunodeficiency The Wiskott–Aldrich immunodeficiency
disorder results from defects in the WASP
protein. WASP is required for actin assem-
bly in a cdc42-dependent manner, and is
required for podosome assembly and
disassembly in primary human
macrophages.
Tau protein Neurological disease Tau protein stabilizes microtubules. Aggre-
gated tau is found in brains of Alzheimer’s
disease patients and therefore has been
postulated to be involved in the progres-
sion of Alzheimer’s disease.
Tau protein Neurological disease Numerous mutations of the tau gene have
been shown to be responsible for fronto-
temporal dementia with Parkinsonsism.
These patients have cytoplasmic inclusions
that include the hyperphosphorylated tau
protein.
MID 1 (midin) Development defect Midin is a microtubule-associated protein
of unknown function. Opitz syndrome is
characterized by abnormal closure of
midline structures.
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 Human Diseases Affecting Intracellular Transport

Potential Trafficking Defects

A number of diseases have been proposed to result from trafficking defects, but their role in intracellular traffic has yet to be
determined. They are listed in this section.

Disease Defective Primary clinical Phenotype and cellular pathology

(reference) gene or manifestation
protein

Huntington’s Huntington Neurological Huntington, Huntington-associated protein, and P150 (glued)

disease (130,131) disease are present in a complex that participates in dynein–dynactin
associated intracellular transport. In addition, Huntington and
Huntington-interacting protein have been localized to
clathrin-coated vesicles.

Hereditary Cationic Pancreatic Effects on intracellular transport have been postulated but not
pancreatitis (132) trypsinogen disease examined.

Autoimmune Diseases that Affect Transport

Hereditary diseases that result from mutations in the essential machinery required for intracellular transport have not yet been
identified, as these would likely result in lethal phenotype. However, such components could potentially be the target for autoimmune
diseases. Autoimmune diseases affecting intracellular transport components are listed in this section.

Disease (reference) Immunogenic Primary clinical Phenotype and cellular pathology

macromolecule manifestation

Anti-phospholipid syndrome Autoimmune disease Autoimmune LBPA is localized to the internal

[reviewed in (133)]
against lysobisphosphatidic
acid (LBPA)
disease membranes of multivesicular bodies, and
has been proposed to constitute a
unique domain for sorting of membrane
proteins. Patients with antibodies against
LBPA demonstrate abnormal retention of
sphingolipids, cholesterol and proteins in
multivesicular bodies.

Overlap connective tissue
disease (134)
Autoimmune disease Autoimmune Nup 180 is a novel protein of unknown
against Nup 180 disease function that is associated with the
nuclear pore complex. Autoantibodies
that are expressed in patients with
overlap connective tissue disease do not
interfere with nuclear translocation.

Sjogren’s syndrome Autoimmune disease Autoimmune Golgin 97 is a Golgi-localized coiled-coil

(135,136) against Golgins, disease domain containing protein that has been
specifically Golgin 97 postulated to be required for Rab6
regulated membrane-tethering events.

Stif-man syndrome (137) Autoimmune disease Autoimmune Amphiphysin I is thought to function in

against Amphiphysin I disease clathrin-mediated endocytosis.

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