Clinical Features
PraderWillis syndrome is a developmental syndrome that includes neonatal hypotonia, hyperphagia and obesity, hypogonadism, small hands and
feet, and mental retardation associated with characteristic behavior. Many individuals with PraderWillis syndrome are hypopigmented but do not have
the typical ocular features of albinism; however,
individuals with PraderWillis syndrome can have
typical features of OCA. For those without OCA, the
hypopigmentation is characterized by hair and skin
that are lighter than unaffected family members.
Childhood nystagmus and strabismus are common
but often do not persist into adult life. The irides
are pigmented with some translucency on globe
transillumination, and retinal pigment is reduced
in amount. Foveal hypoplasia usually is not present, but the fovea may not appear entirely normal.
Visual evoked potential studies have revealed optic
tract misrouting similar to that found in albinism in
some individuals with PraderWillis syndrome and
hypopigmentation, but this is not a universal finding. Some individuals with PraderWillis syndrome
have typical OCA2 with cutaneous hypopigmentation and all ocular features of albinism.
Angelmans syndrome is a complex developmental disorder with developmental delay and severe
mental retardation, microcephaly, neonatal hypotonia, ataxic movements, and inappropriate laughter.
In Angelmans syndrome, the hypopigmentation
is characterized by light skin and hair. Nystagmus
or strabismus may be present early in life, and iris
translucency and reduced retinal pigment may be
present. No analysis of optic nerve formation is
available. As in PraderWillis syndrome, individuals
with Angelmans syndrome who have typical OCA2
features have been described.62
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PATHOGENESIS OF OCA3
The pathogenesis of OCA3 remains poorly understood because the normal function of Tyrp1 in human melanocytes is still being clarified. In murine
melanocytes, Tyrp1 protein appears to function as
DHICA oxidase (Kobayashi et al, 1994). However,
this enzymatic activity has not been observed for
human Tyrp1 protein.68,69 Clearly Tyrp1 is important
for melanosomal melanization, not only because of
the phenotype of the brown mouse, with a TYRP1
mutation and accompanying coat color dilution,
but also because of the pigmentary phenotypes of
patients with OCA3 due to TYRP1 mutations. TYRP1
and tyrosinase reciprocally stabilize each other
through associations in the endoplasmic reticulum,
with mutations in either of them resulting in the
retention and degradation of both in the endoplasmic reticulum, thus reducing their transport to melanosomes.70 This suggests that abnormal trafficking and/or reduced stability of wild-type tyrosinase
elicited by mutant Tyrp1 could be an important
etiologic factor of OCA3.
OCULOCUTANEOUS ALBINISM TYPE 4.
OCA4 (OMIM #606574) is a form of oculocutaneous
albinism (OCA) that may be rather rare worldwide,
but relatively common as a type of albinism in East
Asian populations. A variety of mutations, including a splice-acceptor-site mutation and missense
mutations, have been found in a gene called
MATP (membrane-associated transporter protein),
located on chromosome 5p, in OCA4.71,73 OCA4 can
have a variable phenotype, ranging from absence
of pigmentation to some pigmentation with brown
irides. Pigment darkening during the first decade of
life has been reported.73
The protein product of the MATP gene is predicted
to be a membrane protein spanning the membrane 12 times, and containing a conserved sucrose
transporter signature sequence, suggesting an
important functional role for this motif.72 In addition, melanosome anomalies have been observed
in the medaka fish and in the mouse homologs of
OCA4.72,74 These data indicate that MATP/Matp plays
a critical role in vertebrate pigmentation and suggest that MATP/Matp may be a component of the
melanosomal membrane, presumably mediating
the transport of a molecule required for melanogenesis or for another melanosome function.
MOLECULAR BASIS OF
HPS-5, -6, -7, AND -8 DEFECTS
As members of the BLOC-2 complex,91,92 defects
in HPS5 and HPS6 might be expected to result in
similar cellular dysfunction as mutations in HPS3,
perhaps reflecting the more benign clinical course
of these HPS types. Eight distinct HPS5 mutations
have been found to be associated with HPS5, with
two missense mutations occurring as compound
heterozygous mutations in siblings, rendering it
difficult to determine whether each mutation is
pathogenic or whether one is a polymorphism.157,159
In HPS5 fibroblasts, the distribution of the LAMP-3/
CD63 lysosomal marker was exclusively noted in
the perinuclear region, instead of also being present in the periphery as in normal cells.157
Mutations in DTNBP1, encoding the dysbindin protein, are responsible for HPS7. Dysbindin, together
with proteins palladin, muted, cappuccino, and
BLOC1S3, is a member of the BLOC-1 complex.161
Although dysbindin associates with the - and
-dystrobrevins,163 which are binding partners of
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