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1 From the Riverview Medical Center, Carrabelle, Florida; 2 Oftalmologia Especializada, Santo Domingo, Dominican Republic; the 3 Departments of Genetics and Development and Psychiatry, Columbia Genome Center, College of Physicians and Surgeons at Columbia University and New York Psychiatric Institute, New York; the 4 Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia; and 5 Rockefeller University, Laboratory of Statistical Genetics, New York, New York.
Abstract
PURPOSE. To characterize the disease expression of an autosomal recessive human retinal degeneration associated with a mutation in TULP1 (tubby-like protein 1), a gene with currently unknown function.
METHODS. Homozygotes and heterozygotes from an extended Dominican kindred with a
TULP1 splice-site gene mutation (IVS14+1,G
A) were
studied clinically and with visual function tests. Sequence analysis of
TULP1 was also performed in unrelated patients with
severe retinal degeneration from a North American clinic population.
RESULTS. Homozygotes had nystagmus, visual acuity of 20/200 or worse, color vision disturbances, bull’s eye maculopathy, and peripheral pigmentary retinopathy. Younger patients had a relatively wide extent of kinetic visual fields; older patients had only peripheral islands. No rod function was measurable by psychophysics in any of the patients; markedly reduced cone function was detectable across the visual field of younger patients and in the remaining peripheral islands of older patients. Rod and cone electroretinograms (ERGs) were not detectable using standard methods; microvolt-level cone ERGs were present in some patients. Heterozygotes had normal visual function. No putative pathogenic sequence changes in TULP1 were observed in North American patients with comparably severe retinal phenotypes, mainly in the diagnostic category of Leber congenital amaurosis.
CONCLUSIONS. This TULP1 splice-site mutation in homozygotes causes early-onset, severe retinal degeneration involving macular and peripheral cones and rods. The constellation of phenotypic findings suggests that the TULP1 gene product is critically important for normal photoreceptor function and may play a role in retinal development.
Two lines of research, one into rodent single-gene obesities1 and the other into genetic causes of human retinitis pigmentosa (RP)2 have recently intersected. The result is the discovery that mutations in TULP1 (tubby-like protein 1) can cause forms of human autosomal recessive RP.3 4 5
Tubby (tub) is an autosomal recessive murine
disease with maturity-onset increase in body weight accompanied by
insulin resistance and abnormal glucose tolerance.6
Tub mice, known to be the same as rd5, also have
retinal and cochlear degeneration.7
8
9
10
11
The mutation
associated with tub/rd5 is a GT
transversion that abolishes a donor splice-site, leading to the
replacement of the carboxyl-terminal 44 amino acids with approximately
20 amino acids.12
13
A family of tubby genes is now recognized and includes human TUB (homologue of mouse tub), TULP1, TULP2, and TULP3. The carboxyl-terminal end of tubby gene family members is conserved, and there are related proteins in lower animals and plants. TUB (human chromosome 11p15.4) is expressed in many tissues, but TULP1 (6p21.3) has been found mainly in the retina. TULP2 (19q13.1) is highly expressed in testis but minimally in retina.14 15 TULP3 (12p13.2) has recently been described and is expressed in the eye.15 The function of these proteins is currently unknown.
For several years, we have investigated an autosomal recessive retinal
degeneration in large pedigrees living in the Dominican Republic. A
genomic search for linkage led to the identification and refinement of
a locus on chromosome 6p,16
17
designated
RP14. We recently identified the molecular cause of
retinal degeneration in the Dominican families as a splice-site
mutation (IVS14+1,GA) in the TULP1
gene.3
Simultaneous with our report, two other studies
noted the pathogenicity of TULP1 gene mutations by
candidate gene screening in patients with RP.4
5
None of the reports to date have given detailed descriptions of the
human disease phenotypes associated with TULP1 gene
mutations. To increase understanding of the pathophysiology of
TULP1-related human retinal degeneration, we studied the
disease expression in family members of the large Dominican kindred
with the IVS14+1,GA TULP1 mutation. This extensive
family provides an opportunity to estimate the natural history of the
disease in a cross-sectional investigation. Once the phenotype was
established, the TULP1 gene was screened for mutations
in a sample of North American patients with comparable clinical
presentations and unknown genotype. Results from the present study can
serve as a template for comparison: with the phenotypes of other human
TULP1-associated retinal degenerations to determine
whether there is allele specificity, with work on the
tub/rd5 mouse, and with ongoing in vitro
and genetically engineered animal studies attempting to elucidate the
role of TULP1 in the retina.18
Methods
Subjects
Patients included in this study were from the extended Dominican
kindreds in which RP14 was first mapped to chromosome 6p21.3
and later identified to have a TULP1 gene
mutation.3
16
17
A further group of unrelated patients had
DNA samples screened for mutations in TULP1. Consent for all
procedures was obtained from subjects after the nature of the studies
had been explained. The research procedures were in accordance with
institutional guidelines and the Declaration of Helsinki.
Phenotype Analyses
Clinical Examinations.
A history of medical diseases was obtained by interview of the patients
and their families. Because of the association of the tub
gene with obesity, body weight and height were measured in the patients
and body fat determined (Body Fat Analyzer Model HBF-300; Omron
Healthcare, Vernon Hills, IL). Because of the association of cochlear
degeneration with the tub gene, a portable hearing
test19
(3000 ± 90 Hz; 35 ± 3 dB) was used to
screen patients for hearing loss (Physician HearPen; Starkey
Laboratories, Eden Prairie, MN), and balance was assessed with tandem
walking and standing on one leg with eyes closed.20
Two types of ocular examination were performed: screening exams in 1992 and 1993 and more complete assessments in 1998. In 1992 and 1993, the examinations were to confirm the diagnosis of retinal degeneration and enable molecular genetic analyses to proceed. These examinations occurred in the remote villages of the Dominican Republic where the kindreds lived. Visual acuity was estimated with near vision cards and fundus appearance assessed with indirect ophthalmoscopy. In 1998, patients were transported to an ophthalmology office in Santo Domingo and had a complete eye examination and the following tests: Goldmann kinetic perimetry, Farnsworth D-15 color panel, fundus photography, dark-adapted static threshold perimetry, and electroretinography (ERG).
Perimetry.
Kinetic perimetry was performed with a Goldmann perimeter using V-4e
and I-4e test targets; visual field extent was
quantified.21
Static threshold perimetry in the
dark-adapted state (>2 hours) was performed using an automated
perimeter (Humphrey Field Analyzer, San Leandro, CA) and techniques
similar to those previously described.22
23
24
Chromatic
stimuli were presented by affixing filters (blue, Wratten 47; or red,
Wratten 26) to goggles worn over the test eye; normal controls and
heterozygotes required an additional 2-log-unit neutral density filter
because of the lower thresholds of these subjects. Profiles of
dark-adapted sensitivity at 2o intervals were
measured in the central 60o along the horizontal
meridian. In patients with absolute central scotomas on kinetic
perimetry, function was assessed with a customized
24o x 24o grid of nine
loci (12o spacing) positioned in the peripheral
field. Homozygotes who retained central but unstable fixation and those
with relatively stable eccentric fixation loci were asked to look
toward their finger which was positioned inside the perimeter bowl at
the desired fixation locus. The degree of eccentric fixation was
determined using the Goldmann kinetic perimeter. The patient was asked
to fixate a large target that was moved on the perimeter bowl until the
corneal light reflex was centered on the pupil, viewed through the
telescope; the final location of the target was measured and taken as
the eccentricity of fixation. Rod and cone mediation of stimuli and
normal values at the test locations were determined in controls in the
fully dark-adapted state (n = 6) and during the cone
plateau after a 99% bleach (n = 2).23
All
red results are reported after application of a 5.5-dB correction which
was the mean dark-adapted extramacular sensitivity difference between
blue and red stimuli in normal subjects. Equal sensitivities (-6 to +6
dB, based on 2 SD) to blue and red stimuli were thus considered rod
mediated; based on results in normal subjects acquired at cone plateau,
higher sensitivity to red than blue with a red>blue difference of 20
dB (12–28 dB, based on 2 SD) was considered cone mediated.
Electroretinography.
Full-field ERGs were performed with a computer-based portable
electrodiagnostic system (EPIC-3000; LKC Technologies, Gaithersburg,
MD) and Burian–Allen bipolar contact lens electrodes (Hansen
Ophthalmics, Iowa City, IA) in 16 homozygotes, 2 heterozygotes, and 5
normal subjects (ages, 22–35 years). A handheld Ganzfeld (Kurbisfeld)
with stroboscope and background light was used to deliver the following
four stimuli: dim white flash, dark-adapted (>2 hours), to elicit a
rod ERG b-wave (minimum normal amplitude, 160 µV; maximum normal
implicit time, 92 msec); bright white flash, dark-adapted, to elicit a
mixed rod and cone ERG a-wave (minimum normal amplitude, 112 µV) and
b-wave (minimum normal amplitude, 310 µV); and light-adapted (>9
minutes) cone ERGs elicited with 1 Hz bright white flashes on a white
background (minimum normal b-wave amplitude, 70 µV); and 29 Hz bright
white flashes on the same background (minimum normal peak-to-peak
amplitude, 65 µV; maximum normal timing, 29.5 msec). In patients with
no recordable responses to these stimuli, a special protocol was used
to resolve smaller signals. In this protocol, the stimulus was a 29-Hz
bright white flash presented without background (after approximately 10
minutes of light adaptation). Responses were recorded with an amplifier
bandwidth of 1 to 70 Hz, digitized at 5 kHz, and averaged over >200
cycles. Off-line, ERGs were detrended by subtracting a third-order
polynomial fit to data; peak-to-peak amplitude and timing of the small
signals in patients were estimated by fitting a 29-Hz sinusoid to the
data and allowing the amplitude and the phase to vary. Photoelectric
artifact was ignored in all data manipulations by discarding regions in
the immediate neighborhood of the stimulus.
PCR Reactions and Sequence Analysis
Patients (n = 25) with severe infantile or
childhood onset of retinal degeneration were included in this part of
the study. The patients were examined by one of the authors (SGJ) and
carried the clinical diagnoses of Leber congenital amaurosis (LCA) or
early-onset RP (simplex, multiplex, or autosomal recessive). Patients
had a history of visual disturbance in the first months or years of
life, usually with nystagmus, reduced visual acuity, nondetectable ERGs
and funduscopic evidence of pigmentary retinopathy. These patients were
previously determined not to have RPE65 or CRX
gene mutations25
(Jacobson, unpublished data, 1999). Blood
samples were obtained and DNA extracted.16
The exons of TULP1 were PCR amplified using the primers designed from adjacent intron sequences 50 to 100 bp from the splice site using the PRIMER program.26 The primer sequences and the genomic sequence of TULP1 have been deposited with GenBank under the accession numbers AF034919–AF034923. For all exons, 100 ng genomic DNA was amplified in a 40-µl reaction with 0.2 µM of each primer and 0.2 µM of each dNTP. PCR amplification was performed using a program with cycling conditions (94°C for 1 minute 15 seconds; 30 cycles of 94°C for 30 seconds, 55°C for 30 seconds; 72°C for 1 minute; and 72°C for 8 minutes) in a DNA engine tetrad (PTC-225: MJ Research, Watertown, MA). For exons 2 and 3, 10% dimethyl sulfoxide was added to the PCR reactions. Exons 1 through exon 14 were PCR amplified using 1 U Taq DNA polymerase (Gibco, Grand Island, NY) at a MgCl2 concentration of 1.8 mM, and exon 15 was amplified using 1 U at a MgCl2 Taq DNA polymerase (Gibco) concentration of 1.5 mM. The exons and the exon–intron junctions were sequenced with the primers described above using an automated sequencer (model 373A; ABI). Alignment was performed using software (Sequencher, ver. 3; Gene Codes).
Results
The homozygotes and heterozygotes in this study are shown in the pedigrees of Figure 1 . Pedigrees A and B have been greatly simplified from far more extensive pedigrees including several hundred people who can be traced to two founders born in the early 1800s. Many patients in the present study are multiply related to the founders, but some of the consanguinity could not be readily illustrated. Of the 64 living members depicted in Figure 1 , 52 were genotyped; several heterozygotes and normal relatives were genotyped but are not shown. Forty-two family members shown were assessed for phenotype with either screening tests or more extensive evaluations or both: 27 of 29 homozygotes, 13 of 21 heterozygotes, and 2 normal subjects.
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Ocular Examinations
The limited ocular examinations in 1992 and 1993 of the visually
impaired family members showed they had nystagmus, abnormal visual
acuity and visual fields, and retinal degeneration. Table 1
lists clinical data from the more recent and complete ocular
examinations. By history, homozygotes had childhood onset of night
blindness; relatives reported that night vision problems were evident
in these affected people by age 3 and as young as 10 months of age. The
homozygotes had reduced visual acuity and nystagmus. The nystagmus
appeared to be pendular with both horizontal and rotary components.
Color vision with a Farnsworth D-15 panel was either unmeasurable or
abnormal without a specific axis of confusion. Most patients had myopic
refractive errors. Slit lamp examinations showed vitreous condensations
and cellularity in a minority of patients; the one patient with
cataracts, a 42-year-old man (A, VI-5), had only minimal nuclear
sclerotic changes. Applanation tonometry was normal in all subjects.
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Visual Function
Representative results of kinetic perimetry in patients at
different disease stages are illustrated in Figures 3A
3B
3C
3D
3E
3F
, and the extent of visual field in 15 homozygotes and two
heterozygotes is graphically summarized (Fig. 3G)
. The two
heterozygotes we examined had normal kinetic fields to targets V-4e and
I-4e (Fig. 3A)
. Three of six homozygotes under the age of 18 years
showed either a normal or near normal extent of visual field with the
V-4e target (Fig. 3B)
, whereas the other three had reductions in field
extent with residual field being somewhat elliptical in shape (Fig. 3C)
. There was no detection of the I-4e target in any of the 15
homozygotes tested. Homozygotes more than 18 years of age had more
reduced extent of field; large central scotomas were detectable (Fig. 3D)
, or there were only measurable islands of peripheral vision (Figs. 3E
3F)
. Visual field extent (average of both eyes) plotted against age
indicates substantial but impaired extent of field in the first two
decades of life and a decline in later decades. Best fit exponential to
the data from homozygotes is shown (VF =
10[-0.44(age-8.2)], VF as fraction of mean
normal, age in years).
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Discussion
Central Visual Abnormalities, an Early Feature of This Splice-Site
TULP1 Mutation
The disease associated with the IVS14+1,GA TULP1
gene mutation is an early-onset, severe, retina-wide degeneration.
Central visual dysfunction and nystagmus are characteristic findings at
all stages of the disease. In the first decade of life, there is no
measurable rod function and severely impaired cone function throughout
the retina. A decline in this residual cone vision occurs over the
ensuing decade such that by the third and fourth decades of life, only
islands of peripheral cone-mediated vision remain. At the later stages
of disease, the ophthalmoscopic appearance is that of severe pigmentary
retinopathy with maculopathy.
The nystagmus and reduced visual acuity but relatively wide visual fields in young TULP1 homozygotes indicate that central visual abnormalities are a prominent early feature of the disease expression. This early central visual loss is probably because of central retinal photoreceptor maldevelopment, dysfunction, or degeneration as part of the generalized retinopathy. LCA, for example, is typified by early nystagmus and reduced visual acuity.29 30 Signs of maculopathy, such as annuli of yellow deposits, bull’s eye appearance, and atrophic lesions, eventually become visible by ophthalmoscopy and point to significant central retinal degenerative disease at the photoreceptor and retinal pigment epithelial level.
Do the optic disc changes seen on ophthalmoscopy in some of the patients suggest this TULP1 mutation causes a complicated disease expression involving not only photoreceptors but also more proximal retinal cells or the optic nerve? The most parsimonious explanation for optic disc findings in this TULP1 mutation is that they are a secondary manifestation of a primary photoreceptor disease expression. Optic disc changes in retinal degenerations have traditionally been ascribed to the retinopathies.31 Temporal pallor of the optic disc has been reported in retinal degenerations with early maculopathy such as the cone–rod dystrophies.32
Brief accounts of three other patients representing two different
TULP1 genotypes are in the literature. Two compound
heterozygotes (Arg420Pro, Phe491Leu) in the fourth decade of life were
described as having visual acuity of less than 20/200, only central
islands of visual field remaining, and essentially no detectable
ERGs.4
A homozygote with the IVS14–6,CA mutation, also
in the fourth decade of life, was reported to have constricted visual
fields and no detectable ERG.5
No descriptions of
phenotype were provided for another homozygote
(Lys489Arg),5
a compound heterozygote (Ile459Lys,
IVS2+1,GA),4
and other patients with heterozygous
changes considered pathogenic.4
5
At present, the limited
information on patients other than those with the IVS14+1,GA
TULP1 mutation prevents discussion about possible allele
specificity.
It is notable, however, that the patients found to have
TULP1 mutations by candidate gene screening were from
populations with the clinical diagnosis of RP.4
5
The
retinal degeneration resulting from the IVS14+1,GA TULP1
mutation is an atypical form of RP.33
It is not a
cone–rod dystrophy; although there are macular lesions, early
unmeasurable rod function with residual impaired cone function weighs
against this diagnostic category.34
35
A clinical category
that may describe the disease better is LCA,29
30
a
genetically heterogeneous set of diseases2
with early age
of onset of severe retinal degeneration with nystagmus, visual acuity
loss, and undetectable ERGs. The possibility that the two previous
screenings of patients with RP for TULP1
mutations4
5
may not have included patients with LCA led
us to examine a group of non-Dominican patients fitting into this
disease category. Mutations in TULP1 were not the cause of
LCA in this sample of patients, although we cannot exclude the
possibility that coding sequence variants account for a small fraction
of LCA mutations in other samples or that mutations in the regulatory
sequences of TULP1 contribute to the pathologic course of
LCA. These findings, taken together with results of the other published
candidate gene screenings,4
5
extend the conclusion that
TULP1 is a relatively rare cause of autosomal recessive
retinal degeneration.
Relationship of TULP1-Associated Human Disease to theTub Mouse Phenotype
The exact function is not yet known for any of the
tubby family of genes, members of which currently include
tub, TUB, TULP1, TULP2, and
TULP3.12
13
14
15
It is of interest that the
causative mutations in tub leading to the mouse phenotype
and TULP1 leading to the disease in the patients in this
study are at the identical donor splice site.3
Both
mutations would be expected to alter the evolutionarily conserved
carboxyl-terminal end of these related molecules. From our results,
only the retinal degeneration was known to be shared by the patients
and the tub mouse. The patients were not obese and had no
major impairment of hearing or balance; more extensive testing was not
possible on site in the Dominican Republic.
How does the tub/rd5 retinal degeneration compare with that in patients with the splice-site TULP1 mutation? Early and prominent photoreceptor disease is a shared feature. The murine homozygous phenotype involves a progressive retina-wide rod and cone degeneration; abnormally distorted outer segments are found at 3 weeks, the earliest time studied.7 8 9 10 11 The inner retina has been described as normal.7 8 Similar to human RP36 and other animal models of inherited retinal degeneration,37 38 39 photoreceptor cell death in tub/rd5 occurs by an apoptotic mechanism.18
It is of interest that a recent study found that retinal expression of the tub gene in mice occurs during embryogenesis only in retinal ganglion cells and postnatally only in photoreceptors.40 TULP1 may also play some role in human retinal development and the splice-site mutation could lead to a developmental defect manifesting clinically as visual acuity loss and nystagmus. The profound and early photoreceptor degeneration bespeaks a critical functional role for TULP1 in these cells postnatally or possibly during embryogenesis. Further studies, such as those of genetically engineered murine models of TULP1-associated disease, should help elucidate disease mechanisms. Considering the unique features of structure, function, and development of the primate central retina41 42 and the early central visual losses in patients in this study, investigations to localize precisely the gene product of TULP1 in human adult and fetal retinal tissue should also be of value.
Acknowledgements
The authors thank Dr. Grant Liu for his generous help with interpreting the neuro-ophthalmological findings in the patients; and David Hanna, Kai Zhao, Leigh Gardner, Jason Christopher, and Dr. Rodrigo Montemayor for their help with the studies.
Footnotes
Reprint requests: Samuel G. Jacobson, Scheie Eye Institute, 51 N. 39th Street, Philadelphia, PA 19104.
Supported by a Molecular Genetics Studies Program grant (JO) and a Center Grant (SGJ), The Foundation Fighting Blindness; Grant EY05627 from the National Institutes of Health; The Daniel Matzkin Research Fund; The Chatlos Foundation; the F. M. Kirby Foundation; and the Mackall Trust.
Submitted for publication February 9, 1999; accepted April 1, 1999.
Proprietary interest category: N.
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