RP1-related retinopathy is an inherited retinal dystrophy caused by pathogenic variants in RP1, encoding a 2,156-amino-acid microtubule-associated protein (MAP) localized to the connecting cilium and axoneme of photoreceptors. RP1 contains an N-terminal doublecortin (DCX) domain and a bifocal (BIF) domain and is required for correct orientation and higher-order stacking of the photoreceptor outer segment discs. RP1 has four exons, with the protein-coding region in the last three; exon 4 alone encodes more than 85% of the protein and harbors most known pathogenic variants. Nearly all known pathogenic variants are nonsense or frameshift changes (truncating variants account for roughly 80% of reported pathogenic RP1 alleles), predicted to truncate the protein by roughly 50-70%. RP1 is unusual among retinal dystrophy genes in causing disease through two distinct genetic mechanisms from the same locus: heterozygous truncating variants clustered in the middle of exon 4 act as dominant-negative alleles, causing autosomal dominant retinitis pigmentosa (adRP); biallelic truncating variants located toward the N- or C-terminal ends of exon 4 cause a distinct, generally more severe autosomal recessive retinitis pigmentosa (arRP) through loss of function, though a subset of biallelic exon-2 missense variants can instead cause a considerably later-onset phenotype. Studies excluding haploinsufficiency as the causative mechanism support a dominant-negative model for the heterozygous middle-exon-4 variants instead. No RP1-specific gene therapy is in clinical trials as of 2026; management is supportive.
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name: RP1-Related Retinopathy
creation_date: "2026-08-13T21:00:00Z"
category: Mendelian
description: >-
RP1-related retinopathy is an inherited retinal dystrophy caused by pathogenic
variants in RP1, encoding a 2,156-amino-acid microtubule-associated protein
(MAP) localized to the connecting cilium and axoneme of photoreceptors. RP1
contains an N-terminal doublecortin (DCX) domain and a bifocal (BIF) domain
and is required for correct orientation and higher-order stacking of the
photoreceptor outer segment discs. RP1 has four exons, with the protein-coding
region in the last three; exon 4 alone encodes more than 85% of the protein and
harbors most known pathogenic variants. Nearly all known pathogenic variants are
nonsense or frameshift changes (truncating variants account for roughly 80% of
reported pathogenic RP1 alleles), predicted to truncate the protein by roughly
50-70%. RP1 is unusual among retinal dystrophy genes in causing disease
through two distinct genetic mechanisms from the same locus: heterozygous
truncating variants clustered in the middle of exon 4 act as dominant-negative
alleles, causing autosomal dominant retinitis pigmentosa (adRP); biallelic
truncating variants located toward the N- or C-terminal ends of exon 4 cause a
distinct, generally more severe autosomal recessive retinitis pigmentosa
(arRP) through loss of function, though a subset of biallelic exon-2 missense
variants can instead cause a considerably later-onset phenotype. Studies
excluding haploinsufficiency as the causative mechanism support a
dominant-negative model for the heterozygous middle-exon-4 variants instead.
No RP1-specific gene therapy is in clinical trials as of 2026; management is
supportive.
disease_term:
preferred_term: RP1-related dominant retinopathy
term:
id: MONDO:0800400
label: RP1-related dominant retinopathy
synonyms:
- Retinitis pigmentosa 1
- RP1
- autosomal dominant retinitis pigmentosa due to RP1
- RP1-associated retinal dystrophy
parents:
- Retinitis pigmentosa
- Inherited Retinal Dystrophy
notes: >-
MONDO's own free-text definitions for the two gene-series terms used here
(MONDO:0800399 "RP1-related recessive retinopathy" and MONDO:0800400
"RP1-related dominant retinopathy") appear to have their `def:` fields swapped
relative to their labels (the "recessive" term's definition text describes
dominant inheritance and vice versa) - the `is_a` axioms (autosomal recessive
disease vs. autosomal dominant disease) are internally consistent with the
labels and were used as the source of truth here, not the free-text defs. The
older, more general MONDO:0008377 "retinitis pigmentosa 1" (xref OMIM:180100)
predates the split into dominant/recessive gene-series terms and was not used
as the primary anchor. One Chinese cohort attributed roughly 2% of RP cases to
RP1 (a single-gene share broadly comparable to other major RP genes across
ethnicities). Disease severity generally differs by inheritance: a US
multicenter cohort of biallelic (recessive) patients had symptom onset
ranging 4-30 years of age (mean 14.9, median 13) with macular atrophy common
across the cohort, and a separate Brazilian biallelic cohort reported
diagnosis within the first decade of life with severe visual acuity loss at a
young age; within the US cohort, patients carrying at least one exon-2
missense variant had a considerably later onset than the biallelic-RP1
average. Dominant RP1-RP is generally considered comparatively milder and
later in onset than the recessive form, though a precisely quantified age
range for the dominant form specifically was not found in the sources used
here.
has_subtypes:
- name: Recessive
display_name: RP1-Related Recessive Retinopathy
subtype_term:
preferred_term: RP1-related recessive retinopathy
term:
id: MONDO:0800399
label: RP1-related recessive retinopathy
description: >-
Autosomal recessive RP1-related retinitis pigmentosa caused by biallelic
truncating variants located toward the N- or C-terminal ends of RP1 exon 4,
producing complete loss of functional RP1 protein. This form is generally
more severe than the dominant form: a US multicenter cohort had symptom
onset ranging 4-30 years of age (mean 14.9, median 13) with macular atrophy
common across the cohort, and a separate Brazilian cohort reported
diagnosis within the first decade of life with severely affected visual
acuity at a young age. Patients carrying at least one exon-2 missense
variant can have a considerably later onset than this average.
inheritance:
- name: Autosomal dominant
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
description: >-
Heterozygous truncating variants clustered in the middle portion of RP1
exon 4 act through a dominant-negative mechanism rather than
haploinsufficiency. RP1 accounts for a substantial fraction of autosomal
dominant retinitis pigmentosa. Each child of an affected parent has a 50%
chance of inheriting the pathogenic variant.
evidence:
- reference: PMID:33681214
reference_title: "Dominant RP in the Middle While Recessive in Both the N- and C-Terminals Due to RP1 Truncations: Confirmation, Refinement, and Questions"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "some studies have excluded haploinsufficiency and gain-of-function as the causative mechanism of RP1 variants"
explanation: >-
Establishes that dominant RP1 disease is not caused by simple
haploinsufficiency, supporting a dominant-negative mechanism for
heterozygous truncating variants.
- name: Autosomal recessive
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >-
Biallelic truncating variants toward the N- or C-terminal ends of RP1 exon 4
cause a distinct, more severe autosomal recessive retinitis pigmentosa
through loss of function. Both parents of an affected child are obligate
heterozygous carriers; each sibling has a 25% chance of being affected.
evidence:
- reference: PMID:32565670
reference_title: "Biallelic RP1-associated retinal dystrophies: Expanding the mutational and clinical spectrum"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Biallelic RP1 mutations cause a broad spectrum of retinal disease."
explanation: >-
Reports as a finding that biallelic (not simply heterozygous) RP1
variants cause retinal disease, directly evidencing the autosomal
recessive inheritance modeled by this node.
pathophysiology:
- name: Heterozygous RP1 Dominant-Negative Truncation
description: >-
Heterozygous truncating (nonsense/frameshift) variants clustered in the
middle portion of RP1 exon 4 - which alone encodes more than 85% of the
protein despite RP1 having four exons total - produce a stable, partially
functional truncated protein that retains the N-terminal doublecortin (DCX)
domain but loses distal sequence needed for normal regulation. This
truncated product co-assembles with wild-type RP1 at the photoreceptor
axoneme and interferes with normal microtubule/axoneme organization, a
dominant-negative mechanism rather than simple haploinsufficiency. This is
the more common RP1 disease mechanism and underlies the majority of
RP1-related autosomal dominant RP.
gene:
preferred_term: RP1
modifier: ABNORMAL
term:
id: hgnc:10263
label: RP1
genetic_context:
gene:
preferred_term: RP1
term:
id: hgnc:10263
label: RP1
functional_impact_category: DOMINANT_NEGATIVE
description: >-
Heterozygous middle-exon-4 truncating variants retain the BIF domain and
produce an interfering truncated product rather than simply
haploinsufficient loss of RP1 protein.
cell_types:
- preferred_term: retinal rod cell
term:
id: CL:0000604
label: retinal rod cell
- preferred_term: retinal cone cell
term:
id: CL:0000573
label: retinal cone cell
evidence:
- reference: PMID:33681214
reference_title: "Dominant RP in the Middle While Recessive in Both the N- and C-Terminals Due to RP1 Truncations: Confirmation, Refinement, and Questions"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "the heterozygous variants will cause retinal degeneration with preserved BIF domain but loss of the unrecognized domain"
explanation: >-
Directly supports the dominant-negative model: heterozygous truncations
that retain the BIF domain but lose additional distal sequence cause
retinal degeneration despite the presence of one normal allele,
consistent with an interfering truncated product rather than simple
haploinsufficiency.
- reference: PMID:33681214
reference_title: "Dominant RP in the Middle While Recessive in Both the N- and C-Terminals Due to RP1 Truncations: Confirmation, Refinement, and Questions"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "For the variants associated with adRP, the truncated production will preserve the BIF domain and may cause disease via a dominant-negative effect"
explanation: >-
Directly supports the dominant-negative (rather than haploinsufficient)
mechanism for heterozygous RP1 truncating variants preserving the BIF
domain.
- reference: PMID:33681214
reference_title: "Dominant RP in the Middle While Recessive in Both the N- and C-Terminals Due to RP1 Truncations: Confirmation, Refinement, and Questions"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "the middle portion from c.1981 (p.661) to c.2749 (p.917)"
explanation: >-
Provides the precise coding-sequence/protein coordinates defining the
middle-exon-4 region where heterozygous truncations act as
dominant-negative alleles, refining the "middle portion" claim made by
this node.
downstream:
- target: Photoreceptor Axoneme Disorganization
description: >-
The dominant-negative truncated protein disrupts normal RP1 function at
the axoneme regardless of the co-expressed wild-type allele.
- name: Biallelic RP1 Loss
description: >-
Biallelic truncating variants located toward the N- or C-terminal ends of
RP1 exon 4 (distinct from the middle-clustered dominant variants) produce
complete loss of functional RP1 protein when present on both alleles.
Heterozygous carriers of these same terminal variants are clinically
unaffected, confirming that a single functional RP1 allele is sufficient
for normal photoreceptor structure and that recessive disease requires
complete loss rather than a dominant-negative product.
gene:
preferred_term: RP1
modifier: ABSENT
term:
id: hgnc:10263
label: RP1
genetic_context:
gene:
preferred_term: RP1
term:
id: hgnc:10263
label: RP1
functional_impact_category: LOSS_OF_FUNCTION
description: >-
Biallelic N-/C-terminal truncating variants produce complete loss of
functional RP1 protein; a single functional allele is sufficient for
normal photoreceptor structure, so disease requires loss of both alleles.
cell_types:
- preferred_term: retinal rod cell
term:
id: CL:0000604
label: retinal rod cell
- preferred_term: retinal cone cell
term:
id: CL:0000573
label: retinal cone cell
evidence:
- reference: PMID:32005865
reference_title: "Retinitis Pigmentosa Due to Rp1 Biallelic Variants"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "They had classic retinitis pigmentosa with diagnosis at the first decade of life. The visual acuities were severely affected at a young age."
explanation: >-
Documents the severe, early-onset phenotype resulting from biallelic RP1
loss-of-function variants, consistent with complete loss of RP1 function.
- reference: PMID:33681214
reference_title: "Dominant RP in the Middle While Recessive in Both the N- and C-Terminals Due to RP1 Truncations: Confirmation, Refinement, and Questions"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Heterozygous truncations alone in the N- and C- terminals were unlikely pathogenic."
explanation: >-
A described negative control: this cohort's single heterozygous
N-/C-terminal truncations were not enriched in RP patients and were
judged unlikely pathogenic, directly supporting the claim that one
functional RP1 allele is sufficient and that biallelic loss is required
for recessive disease.
downstream:
- target: Photoreceptor Axoneme Disorganization
description: >-
Complete absence of functional RP1 protein disrupts axoneme organization
more severely and from an earlier age than the dominant-negative
mechanism.
- name: Photoreceptor Axoneme Disorganization
description: >-
RP1 is a photoreceptor-specific microtubule-associated protein located in
the connecting cilium and axoneme, where it controls the length and
stability of the axoneme and is required for correct orientation and
higher-order stacking of outer segment discs. Loss of functional RP1 (via
either the dominant-negative or recessive loss-of-function mechanism)
disrupts this scaffolding role, producing misoriented, disorganized outer
segment discs.
cellular_components:
- preferred_term: ciliary transition zone
term:
id: GO:0035869
label: ciliary transition zone
cell_types:
- preferred_term: retinal rod cell
term:
id: CL:0000604
label: retinal rod cell
biological_processes:
- preferred_term: cilium assembly
modifier: ABNORMAL
term:
id: GO:0060271
label: cilium assembly
evidence:
- reference: PMID:15269252
reference_title: "The Retinitis Pigmentosa 1 Protein Is a Photoreceptor Microtubule-Associated Protein"
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Disruption of the Rp1 gene in mice causes misorientation of outer segment discs, suggesting a role for RP1 in outer segment organization."
explanation: >-
Establishes RP1's structural role in outer segment disc organization
using the Rp1 knockout mouse model; loss of RP1 causes disc
misorientation, the direct structural consequence modeled by this node.
- reference: PMID:15269252
reference_title: "The Retinitis Pigmentosa 1 Protein Is a Photoreceptor Microtubule-Associated Protein"
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "we show that the RP1 protein is part of the photoreceptor axoneme"
explanation: >-
Establishes the subcellular localization of RP1 to the connecting
cilium/axoneme, the structure disrupted in this node.
downstream:
- target: Rod Photoreceptor Apoptosis
description: >-
Disorganized, misoriented outer segment discs impair photoreceptor
function and structural integrity over time, driving progressive rod
photoreceptor degeneration.
- name: Rod Photoreceptor Apoptosis
conforms_to: "photoreceptor_degeneration#Rod Photoreceptor Apoptosis"
description: >-
Progressive structural disorganization of the outer segment from
dysfunctional RP1 ultimately drives rod photoreceptor apoptosis, the
hallmark rod-predominant degeneration of retinitis pigmentosa producing
nyctalopia and progressive peripheral visual field loss. Secondary cone
degeneration follows as rods are lost. The recessive form progresses far
more rapidly and with earlier macular involvement than the dominant form.
cell_types:
- preferred_term: retinal rod cell
term:
id: CL:0000604
label: retinal rod cell
biological_processes:
- preferred_term: neuron apoptotic process
modifier: INCREASED
term:
id: GO:0051402
label: neuron apoptotic process
evidence:
- reference: "ORPHA:791"
reference_title: "Retinitis pigmentosa"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Retinitis pigmentosa (RP) is an inherited retinal dystrophy leading to progressive loss of the photoreceptors and retinal pigment epithelium and resulting in blindness usually after several decades."
explanation: >-
Orphanet establishes progressive photoreceptor loss as the defining
pathophysiological feature of retinitis pigmentosa, including RP1-RP.
phenotypes:
- category: Ophthalmologic
name: Progressive Night Blindness
frequency: VERY_FREQUENT
description: >-
Nyctalopia is the earliest and most common presenting symptom of RP1-related
RP, reflecting rod-predominant photoreceptor dysfunction. Onset is generally
earlier and more severe in recessive disease (reported cohort means in the
early-to-mid teens) than in the comparatively milder, later-onset dominant
form.
phenotype_term:
preferred_term: Progressive night blindness
term:
id: HP:0007675
label: Progressive night blindness
evidence:
- reference: "ORPHA:791"
reference_title: "Retinitis pigmentosa"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "HP:0007675 | Progressive night blindness | Very frequent (99-80%)"
explanation: >-
Orphanet records progressive night blindness as a very frequent feature
of retinitis pigmentosa.
- reference: PMID:20301590
reference_title: "Nonsyndromic Retinitis Pigmentosa Overview."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Describe the clinical characteristics of nonsyndromic retinitis
pigmentosa
explanation: >-
GeneReviews' clinical-characteristics scope for nonsyndromic RP,
including RP1-related forms, covers presenting symptoms such as
nyctalopia.
- category: Ophthalmologic
name: Peripheral Visual Field Loss
frequency: FREQUENT
description: >-
Progressive constriction of the visual field from the midperiphery inward
as rod photoreceptors are lost, a cardinal feature of RP1-related RP.
phenotype_term:
preferred_term: Peripheral visual field loss
term:
id: HP:0007994
label: Peripheral visual field loss
evidence:
- reference: "ORPHA:791"
reference_title: "Retinitis pigmentosa"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "HP:0007994 | Peripheral visual field loss | Frequent (79-30%)"
explanation: >-
Orphanet records peripheral visual field loss as a frequent phenotype of
retinitis pigmentosa.
- category: Ophthalmologic
name: Bone Spicule Pigmentation of the Retina
frequency: VERY_FREQUENT
description: >-
Characteristic mid-peripheral intraretinal pigment clumping on funduscopy,
a hallmark sign of RP1-related RP as in other rod-cone dystrophies.
phenotype_term:
preferred_term: Bone spicule pigmentation of the retina
term:
id: HP:0007737
label: Spicular pigmentation of the retina
evidence:
- reference: "ORPHA:791"
reference_title: "Retinitis pigmentosa"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "HP:0007737 | Bone spicule pigmentation of the retina | Very frequent (99-80%)"
explanation: >-
Orphanet records bone spicule retinal pigmentation as a very frequent
finding in retinitis pigmentosa.
- category: Ophthalmologic
name: Attenuation of Retinal Blood Vessels
frequency: FREQUENT
description: >-
Progressive retinal arteriolar narrowing, part of the classic RP fundus
triad alongside bone spicule pigmentation and disc pallor.
phenotype_term:
preferred_term: Attenuation of retinal blood vessels
term:
id: HP:0007843
label: Attenuation of retinal blood vessels
evidence:
- reference: "ORPHA:791"
reference_title: "Retinitis pigmentosa"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "HP:0007843 | Attenuation of retinal blood vessels | Frequent (79-30%)"
explanation: >-
Orphanet records retinal vascular attenuation as a frequent feature of RP.
- category: Ophthalmologic
name: Optic Disc Pallor
frequency: FREQUENT
description: >-
Waxy pallor of the optic disc from nerve fiber layer loss, completing the
classic RP funduscopic triad.
phenotype_term:
preferred_term: Optic disc pallor
term:
id: HP:0000543
label: Optic disc pallor
evidence:
- reference: "ORPHA:791"
reference_title: "Retinitis pigmentosa"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "HP:0000543 | Optic disc pallor | Frequent (79-30%)"
explanation: >-
Orphanet records optic disc pallor as a frequent finding in RP.
- category: Ophthalmologic
name: Abnormal Electroretinogram
frequency: VERY_FREQUENT
description: >-
Full-field ERG shows reduced-to-extinguished rod responses preceding cone
involvement, the diagnostic cornerstone of RP1-related RP.
phenotype_term:
preferred_term: Abnormal electroretinogram
term:
id: HP:0000512
label: Abnormal electroretinogram
reports_on:
- target: Photoreceptor Axoneme Disorganization
relationship: READOUT_OF
endpoint_context: DIAGNOSTIC
interpretation: Full-field ERG measures rod (and later cone) photoreceptor function, which declines as axoneme/outer-segment disorganization progresses.
evidence:
- reference: "ORPHA:791"
reference_title: "Retinitis pigmentosa"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "HP:0000512 | Abnormal electroretinogram | Very frequent (99-80%)"
explanation: >-
Orphanet records abnormal ERG as a very frequent finding in RP.
- category: Ophthalmologic
name: Reduced Visual Acuity
subtype: Recessive
frequency: VERY_FREQUENT
description: >-
Recessive RP1-RP causes severe, early visual acuity loss, in contrast to
the generally milder and later-onset acuity loss typical of dominant
RP1-RP.
phenotype_term:
preferred_term: Reduced visual acuity
term:
id: HP:0007663
label: Reduced visual acuity
evidence:
- reference: PMID:32005865
reference_title: "Retinitis Pigmentosa Due to Rp1 Biallelic Variants"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "They had classic retinitis pigmentosa with diagnosis at the first decade of life. The visual acuities were severely affected at a young age."
explanation: >-
Documents the severe, early-onset visual acuity loss characteristic of
recessive RP1-RP in a biallelic-variant cohort.
- reference: PMID:33681214
reference_title: "Dominant RP in the Middle While Recessive in Both the N- and C-Terminals Due to RP1 Truncations: Confirmation, Refinement, and Questions"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "patients with arRP due to biallelic RP1 variants had a significantly earlier age at onset"
explanation: >-
Genotype-phenotype comparison in this pooled cohort found significantly
earlier age at onset for biallelic (recessive) RP1 patients than for
heterozygous (dominant) RP1 patients, a quantified statistic supporting
the earlier/more-severe recessive course modeled by this node.
- category: Ophthalmologic
name: Macular Atrophy
subtype: Recessive
frequency: VERY_FREQUENT
description: >-
Macular atrophy, with secondary macular involvement, is a common to
near-universal finding in biallelic (recessive) RP1-RP cohorts, and
contributes to the more severe visual outcome of the recessive form
relative to dominant disease.
phenotype_term:
preferred_term: Macular atrophy
term:
id: HP:0007401
label: Macular atrophy
evidence:
- reference: PMID:32565670
reference_title: "Biallelic RP1-associated retinal dystrophies: Expanding the mutational and clinical spectrum"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Macular atrophy was a common feature across the cohort."
explanation: >-
Directly reports macular atrophy as a common feature (FREQUENT band)
across this biallelic RP1 cohort.
- reference: PMID:32005865
reference_title: "Retinitis Pigmentosa Due to Rp1 Biallelic Variants"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Macular atrophy was found in almost all patients"
explanation: >-
Reports macular atrophy in almost all patients of this biallelic RP1
cohort, mapping to the VERY_FREQUENT band under the DisMech qualitative
frequency mapping.
- category: Ophthalmologic
name: Progressive Visual Loss
frequency: VERY_FREQUENT
description: >-
Progressive loss of vision over decades is the natural history of RP1-RP in
both inheritance forms, though the recessive form progresses faster and
from an earlier baseline than the generally milder, later-onset dominant
form.
phenotype_term:
preferred_term: Progressive visual loss
term:
id: HP:0000529
label: Progressive visual loss
evidence:
- reference: "ORPHA:791"
reference_title: "Retinitis pigmentosa"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Retinitis pigmentosa (RP) is an inherited retinal dystrophy leading to progressive loss of the photoreceptors and retinal pigment epithelium and resulting in blindness usually after several decades."
explanation: >-
Orphanet establishes progressive photoreceptor loss over decades as the
defining natural history of retinitis pigmentosa, including RP1-RP.
genetic:
- name: RP1 pathogenic variants
gene_term:
preferred_term: RP1
term:
id: hgnc:10263
label: RP1
association: Causative
features: >-
Nearly all known pathogenic variants are nonsense or frameshift changes
clustered in RP1's coding exons, predominantly exon 4 (which alone encodes
more than 85% of the 2,156-amino-acid protein despite RP1 having four exons
total), predicted to truncate the protein by approximately 50-70%. Variants
located in the middle portion of exon 4 act as heterozygous dominant-negative alleles
causing autosomal dominant RP; variants toward the N- or C-terminal ends of
exon 4 require biallelic inheritance to cause the generally more severe
autosomal recessive form (with exon-2 missense variants forming a
later-onset exception). Studies have excluded simple haploinsufficiency as
the causative mechanism for the dominant form.
inheritance:
- name: Autosomal dominant
evidence:
- reference: PMID:33681214
reference_title: "Dominant RP in the Middle While Recessive in Both the N- and C-Terminals Due to RP1 Truncations: Confirmation, Refinement, and Questions"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "truncations in the middle portion are associated with adRP, while those in the N- and C- terminals are responsible for arRP, which was supported by most truncation variants (91.9%, 147/160)"
explanation: >-
Confirms that RP1 truncating-variant position (middle exon 4 vs.
N-/C-terminal) predicts inheritance pattern (dominant vs. recessive)
in 91.9% (147/160) of reported truncations, the positional rule
underlying this entry's dominant-negative-versus-loss-of-function
model.
- name: Autosomal recessive
evidence:
- reference: PMID:32005865
reference_title: "Retinitis Pigmentosa Due to Rp1 Biallelic Variants"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "They had classic retinitis pigmentosa with diagnosis at the first decade of life. The visual acuities were severely affected at a young age."
explanation: >-
Documents a cohort of patients with biallelic RP1 variants presenting
with early-onset autosomal recessive RP.
evidence:
- reference: PMID:15269252
reference_title: "The Retinitis Pigmentosa 1 Protein Is a Photoreceptor Microtubule-Associated Protein"
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "RP1 is a MAP. Given the specific expression of RP1 in photoreceptors, RP1 is thus the first photoreceptor-specific MAP to be identified."
explanation: >-
Establishes RP1 as a photoreceptor-specific microtubule-associated
protein, the functional basis for its role in RP.
diagnosis:
- name: Full-Field Electroretinography (ERG)
description: >-
Full-field ERG is the diagnostic cornerstone for RP1-related RP, showing a
rod-cone pattern of dysfunction that is milder and later-onset in dominant
disease than in recessive disease.
diagnosis_term:
preferred_term: electroretinogram procedure
term:
id: NCIT:C101217
label: Retinal Examination
evidence:
- reference: "ORPHA:791"
reference_title: "Retinitis pigmentosa"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "HP:0000512 | Abnormal electroretinogram | Very frequent (99-80%)"
explanation: >-
The very high frequency of abnormal ERG in RP supports ffERG as a core
diagnostic investigation for RP1-RP.
- name: Molecular Genetic Testing
description: >-
Sequencing of RP1's coding exons - particularly exon 4, which alone encodes
more than 85% of the protein and harbors most known pathogenic variants -
identifies the truncating variants responsible for both dominant and
recessive disease. Variant position within exon 4 (middle vs. terminal) and
zygosity together determine expected inheritance pattern and prognosis,
informing genetic counseling.
diagnosis_term:
preferred_term: genetic testing
term:
id: NCIT:C15709
label: Genetic Testing
evidence:
- reference: PMID:33681214
reference_title: "Dominant RP in the Middle While Recessive in Both the N- and C-Terminals Due to RP1 Truncations: Confirmation, Refinement, and Questions"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "RP1 is listed as the top seventh of the most frequently implicated genes in inherited retinal disease based on a large cohort."
explanation: >-
Supports the clinical value of including RP1 in molecular genetic
testing panels for inherited retinal disease given its high frequency.
- reference: PMID:20301590
reference_title: "Nonsyndromic Retinitis Pigmentosa Overview."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Provide an evaluation strategy to identify the genetic cause of
nonsyndromic retinitis pigmentosa in a proband
explanation: >-
GeneReviews frames molecular genetic testing as the evaluation strategy
for identifying the genetic cause of nonsyndromic RP, including RP1.
treatments:
- name: Low Vision Rehabilitation
therapeutic_modality: OTHER
description: >-
Low vision aids, orientation and mobility training, and adaptive technology
are the mainstay of management for RP1-related RP, particularly important
for the early and severe visual loss of recessive disease.
treatment_term:
preferred_term: supportive care
term:
id: NCIT:C15747
label: Supportive Care
target_phenotypes:
- preferred_term: Progressive visual loss
term:
id: HP:0000529
label: Progressive visual loss
evidence:
- reference: "ORPHA:791"
reference_title: "Retinitis pigmentosa"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Retinitis pigmentosa (RP) is an inherited retinal dystrophy leading to progressive loss of the photoreceptors and retinal pigment epithelium and resulting in blindness usually after several decades."
explanation: >-
Progressive visual impairment in RP justifies ongoing low-vision
rehabilitation as the primary symptomatic management strategy.
- reference: PMID:20301590
reference_title: "Nonsyndromic Retinitis Pigmentosa Overview."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Provide a brief summary of management of nonsyndromic retinitis
pigmentosa
explanation: >-
GeneReviews includes a management summary for nonsyndromic RP,
including RP1-related forms, of which low vision rehabilitation is a
core component.
- name: Genetic Counseling
therapeutic_modality: OTHER
description: >-
Essential given RP1's unusual dual inheritance pattern: counseling must
distinguish the 50% recurrence risk and generally milder course of
dominant disease from the 25% recurrence risk and generally more severe
course of recessive disease, which depend on where in exon 4 (and, for
biallelic variants, whether an exon-2 missense allele is involved) the
family's variant(s) fall.
treatment_term:
preferred_term: Genetic Counseling
term:
id: NCIT:C15240
label: Genetic Counseling
evidence:
- reference: PMID:22317909
reference_title: "RP1 and retinitis pigmentosa: report of novel mutations and insight into mutational mechanism"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "RP1 is one of the earliest identified disease genes in RP with mutations in this gene known to act both recessively and dominantly although the mutational mechanism remains unclear."
explanation: >-
RP1's dual inheritance pattern, with mechanism-dependent recurrence risk,
underscores the need for genotype-specific genetic counseling.
- reference: PMID:20301590
reference_title: "Nonsyndromic Retinitis Pigmentosa Overview."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Inform genetic risk assessment of family members of a proband with
nonsyndromic retinitis pigmentosa
explanation: >-
GeneReviews explicitly scopes this overview to inform genetic risk
assessment of family members, the core purpose of genetic counseling
modeled by this node.
references:
- reference: PMID:15269252
title: "The Retinitis Pigmentosa 1 Protein Is a Photoreceptor Microtubule-Associated Protein"
- reference: PMID:33681214
title: "Dominant RP in the Middle While Recessive in Both the N- and C-Terminals Due to RP1 Truncations: Confirmation, Refinement, and Questions"
- reference: PMID:22317909
title: "RP1 and retinitis pigmentosa: report of novel mutations and insight into mutational mechanism"
- reference: PMID:32005865
title: "Retinitis Pigmentosa Due to Rp1 Biallelic Variants"
- reference: PMID:32565670
title: "Biallelic RP1-associated retinal dystrophies: Expanding the mutational and clinical spectrum"
- reference: PMID:20664799
title: "Differential pattern of RP1 mutations in retinitis pigmentosa."
- reference: PMID:20301590
title: "Nonsyndromic Retinitis Pigmentosa Overview."
tags:
- GeneReviews
- reference: "ORPHA:791"
title: "Retinitis pigmentosa"