This is a shared mechanism module, not a disease.
Disorder-specific substitutions at the trigger node, grouped by which step of the melanosome life cycle the lost component serves:
1. Cargo delivery during biogenesis - the BLOC-1, BLOC-2 and BLOC-3 complexes
and adaptor protein complex AP-3 (Hermansky-Pudlak syndrome, HPS1-HPS11).
Melanogenic enzymes and structural cargo are not routed into the maturing
melanosome, so the organelle forms but is not properly loaded.
2. Organelle size and fission control - LYST (Chediak-Higashi syndrome). The
giant inclusion bodies that are the diagnostic hallmark are LROs that have
failed to be resolved into normal-sized organelles, and cargo is
mis-sorted into them.
3. Peripheral capture and positioning - the RAB27A-melanophilin-myosin Va
tripartite complex (Griscelli syndrome types 2, 3 and 1 respectively).
The melanosome is built and pigmented normally but is never tethered at
the dendrite tip for transfer.
Curate the specific step; do not describe all three as "defective melanosome biogenesis", which is true only of the first.
**Critical negative boundary: oculocutaneous albinism does NOT conform.** In OCA the lesion is in melanin *synthesis* (TYR, TYRP1, OCA2, SLC45A2) - the melanosome and its trafficking machinery are intact and the organelle is simply empty. Here the opposite holds: pigment is synthesized and retained, so affected melanocytes are *more* densely pigmented than normal while the skin is less so. That inversion, visible on skin histology as melanin-distended melanocytes beside melanin-free keratinocytes, is the single most useful discriminator and the reason this module and the albinism mechanism must not be merged. A disorder whose hypopigmentation comes from absent melanin synthesis does not conform no matter how similar the clinical picture.
Distinct from `lysosomal_substrate_accumulation`. That module models the conventional lysosome failing to degrade what it receives; this one models specialized lysosome-*related* organelles failing to be built, sized, or positioned. A conforming entry here has no storage material and no hydrolase deficiency.
Not an Xogenesis module: the terminal output is the failure of a normal delivery process, not the formation of a pathological anatomical entity. The Chediak-Higashi giant granule is the one arguable exception - it is a new, pathological structure - but it is an intermediate in this chain rather than its endpoint, and it is a malformed normal organelle rather than a derived new formation, so no anchor stanza is asserted.
Conformance requires evidencing a trafficking or biogenesis lesion in the LRO machinery. Hypopigmentation alone, or expression of an LRO gene in melanocytes, is not sufficient.
**Attachment points differ, and the difference is informative.** Only the Griscelli route conforms at the central effector, because only there is the melanosome fully built and pigmented and simply never delivered. In Hermansky-Pudlak syndrome the melanosome *is* transferred - it is merely under-loaded, so melanin production itself is reduced - and the entry therefore conforms at the trigger, the melanosome arm and the other-LRO arm but NOT at the delivery node. Chediak-Higashi sits between the two: its giant melanosomes are abnormally distributed and transfer poorly, and its entry attaches at the melanosome arm. Do not "tidy" these into uniform conformance at the central effector; the disagreement is a real statement about where each disorder's pigmentary failure lies, and flattening it would assert something the evidence does not support.
Interrupted Melanosome Maturation or Peripheral Positioning
amplifier
The melanosome fails at one of three steps. Its melanogenic and structural cargo is not routed in, so the organelle is built but not loaded; or its size and fission are uncontrolled, so it enlarges into a giant granule with mis-sorted contents; or it matures normally but is never captured at the dendrite tip, because the RAB27A-melanophilin-myosin Va complex that tethers it to peripheral actin is broken. The three are not interchangeable, and a conforming entry should name which one it has.
Downstream
-
Failed Delivery of Functional Melanosomes to Keratinocytes
A melanosome that is unloaded, malformed, or unpositioned cannot be transferred to the keratinocyte.
Show evidence (2 references)
"The CHS hallmark is the occurrence of giant inclusion bodies and organelles in a variety of cell types, and protein sorting defects into these organelles."
Documents the size-and-sorting route: LROs that fail to be resolved into normal-sized organelles, with cargo mis-sorted into them.
"Once synthesized in the cell body of the epidermal melanocyte, pigmented melanosomes are translocated down the dendrites and captured at the dendritic tips via various cytoskeletal elements. Molecules recently identified that participate in this process consist of Rab27a, myosin-Va and melanophilin."
Documents the peripheral-capture route and names the tripartite complex whose loss defines the Griscelli entry into this module.
Failed Delivery of Functional Melanosomes to Keratinocytes
central effector
Functional, pigment-bearing melanosomes are not transferred from the melanocyte to surrounding keratinocytes. This is the rate-limiting, disorder-agnostic node of the module: all three upstream routes converge here, and conformance should be declared against it. Because skin and hair are almost entirely keratinocyte, visible pigmentation depends on this transfer and not on melanin synthesis alone - which is why the disorders in this module are hypopigmented despite making normal or excess pigment.
Downstream
-
Hypopigmentation with Syndrome-Specific Extracutaneous Disease
Skin and hair receiving no melanosomes are hypopigmented and photounprotected.
Show evidence (2 references)
"This latter process is absolutely required for visible pigmentation and effective photo-protection because it serves to disperse the pigment in skin and hair."
Establishes that transfer to keratinocytes, not melanin synthesis, is what makes pigmentation visible - the reason this node is the module's rate-limiting step.
"The melanocytes were large and distended with a large volume of melanin (Figure 2). The adjacent keratinocytes were completely devoid of melanin."
Demonstrates this node in patient skin, and demonstrates the inversion that separates the module from albinism: pigment is made and retained rather than absent.