Abstract
purpose. The 208delG (c.72delG, p.Thr25GlnfsX120) mutation in the FSCN2 gene was reported to cause autosomal dominant retinitis pigmentosa (ADRP) and autosomal dominant macular degeneration (ADMD). The purpose of this study was to detect the 208delG mutation in Chinese individuals, with or without hereditary retinal degeneration.
methods. DNA fragments encompassing the 208delG mutation were amplified by polymerase chain reaction (PCR). The amplicons were analyzed by sequencing or/and heteroduplex- single-strand conformational polymorphism (SSCP) analysis. An ophthalmic evaluation was conducted in those individuals with the 208delG mutation.
results. The 208delG mutation was detected in 8 of 242 unrelated probands: 175 with retinitis pigmentosa (RP), 20 with Leber congenital amaurosis (LCA), and 47 with cone–rod dystrophy (CORD). Of the eight, the retinal diseases were RP in six probands, LCA in one proband, and CORD in one proband. The disease was transmitted as an autosomal dominant (one family), autosomal recessive (two families), or sporadic (five families) trait. The mutation did not cosegregate with retinal degeneration in three families, whereas five normal family members also had the mutation. In addition, this mutation was also detected in 13 of 521 unrelated control subjects.
conclusions. The 208delG mutation in FSCN2 is not associated with hereditary retinal degeneration in the Chinese individuals examined, which contradicts the original report about mutation in FSCN2 as a cause of ADRP and ADMD. This finding reminds us that great care is needed in making mutation–disease associations.
Hereditary retinal degeneration is a group of severe disorders affecting vision, which can be transmitted as an autosomal dominant, autosomal recessive, or X-linked trait. Several loci or genes responsible for retinal degeneration have been reported (RetNet, http://www.sph.uth.tmc.edu/Retnet/ provided in the public domain by the University of Texas Houston Health Science Center, Houston, TX).
FSCN2 (OMIM 607643; Online Mendelian Inheritance in Man; http://www.ncbi.nlm.nih.gov/Omim/ provided in the public domain by the National Center for Biotechnology Information, Bethesda, MD), mapped to 17q25, encodes a photoreceptor-specific fascin that belongs to the family of actin-binding proteins. This protein most likely assembles the actin microfilaments associated with photoreceptor discs.
1 A novel locus (RP17) for ADRP has been mapped to 17q25.
2 FSCN2 is therefore considered to be a good candidate for RP17 but has been excluded as a causative gene. Subsequently, genomic sequences of
FSCN2 in 420 unrelated Japanese patients with retinitis pigmentosa were screened. A single mutation, previously designated as 208delG, now c.72delG, p.Thr25GlnfsX120 according to the current recommendation of the Human Genome Variation Society (HGVS; http://www.hgvs.org/mutnomen/ St.Vincent’s Hospital Melbourne, Fitzroy VIC, Australia), was identified in four unrelated Japanese families with ADRP.
3 This mutation was further detected in 2 of 54 unrelated Japanese families with autosomal dominant cone–rod dystrophy or macular degeneration.
4
It would be interesting to know whether the 208delG in FSCN2 represents a mutation hot spot or a mutation founder in certain populations. In light of the close ethnic relation of Chinese and Japanese, evaluation of the 208delG mutation in Chinese patients with retinitis pigmentosa (RP) or other related diseases would be logical. We analyzed the 208delG mutation in 242 unrelated patients with retinal degeneration (including 175 with RP, 47 with CORD [cone–rod dystrophy], and 20 with LCA [Leber congenital amaurosis]) and 521 unrelated control subjects. Surprisingly, the 208delG mutation was detected in 8 of the 242 patients with retinal degeneration, but it did not cosegregate with retinal degeneration in three Chinese families. In addition, this mutation was detected in 13 of 521 unrelated individuals, who do not have any type of hereditary retinal degeneration.
In this study, the 208delG mutation in FSCN2 was detected in 8 of 242 patients with retinal degeneration. The mutation in three families is apparently not associated with the disease, in that five normal family members also had the mutation. The mutation was also detected in 13 of 521 control individuals.
Previously, the 208delG mutation in
FSCN2 was detected in only six Japanese families: four with ADRP and two with ADMD.
3 4 Subsequently, a mouse model involving targeted disruption of the
FSCN2 gene was constructed by replacing exon 1 of
FSCN2 with the cDNA of a green fluorescent protein. It was suggested that haploinsufficiency of the
FSCN2 gene results in retinopathy in the
FSCN2 knockout mice.
8 Unfortunately, the phenotype of mice with homozygous knockout of
FSCN2 has not been reported.
FSCN2 was excluded as a candidate gene for RP17 mapped to this region.
1 2 The 208delG mutation was not detected in 458 families with retinal degeneration from other ethnic groups so far reported.
9 10 11 This mutation was not detected in 215 Spanish probands with ADRP (200 cases) or ADMD (15 cases).
9 It was not detected in 43 Italian families with ADRP
10 or in 200 U.S. families with ADRP in a recent study.
11 In addition, no other mutation, other than 208delG, has been identified in the
FSCN2 gene of patients with retinal degeneration.
3 4 9 10
It is unusual that a gene is a responsible for disease in one ethnic group but not in many others, if a reasonable number of cases have been studied. It is highly unusual that the same mutation can cause both rod–cone and cone–rod retinal degeneration, although different mutations in the same gene have been reported to cause both types of retinal degeneration. In this case, careful and extensive re-evaluation of a larger number of control subjects and unaffected family members is of the first priority. It is almost impossible to claim a disease-causing mutation if it is equally distributed in normal individuals and in patients. Our results indicate that the 208delG mutation was not associated with RP, CORD, and LCA in the Chinese population studied. Further studies in other populations are needed to clarify the different findings in Japanese and Chinese populations. If our result is supported by further studies, it is advised that care be taken in correlating a mutation with a disease until confirmed by multiple findings.
Supported by Grant Z19-01-04-02 from the 863 Plan of China; Grant 010765 from the Guangdong Natural Science Foundation; Grant 6041 from the Fok Ying Tung Education Foundation; and Grant Q02028 from the Guangdong Education Bureau for Excellent Talent.
Submitted for publication June 16, 2006; revised September 28, 2006; accepted December 15, 2006.
Disclosure:
Q. Zhang, None;
S. Li, None;
X. Xiao, None;
X. Jia, None;
X. Guo, None
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked “
advertisement” in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Corresponding author: Qingjiong Zhang, Ophthalmic Genetics and Molecular Biology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 54 Xianlie Road, Guangzhou 510060, China;
[email protected].
Table 1. The 208delG Mutation Detected in Patients and Control Subjects
Table 1. The 208delG Mutation Detected in Patients and Control Subjects
Subjects | With Mutation | Without Mutation | Total |
Patients* | | | 242 |
RP | 6 | 169 | |
LCA | 1 | 19 | |
CORD | 1 | 46 | |
Control subjects | | | 521 |
Normal | 9 | 320 | |
LHON, † | 4 | 188 | |
Total | 21 | 742 | 763 |
Table 2. Clinical Information on Individuals with the 208delG Mutation
Table 2. Clinical Information on Individuals with the 208delG Mutation
ID | Gender | Age (y) | Age at Onset | First Symptom | Visual Acuity | Phenotype | ERG Recording | |
| | | | | | | Rod Response | Cone Response |
Affected probands | | | | | | | | |
A | M | 13 | Infancy | Poor vision | 0.02; 0.01 | LCA* | None identifiable | None identifiable |
B | M | 16 | 9 y | Night blindness | 0.04; 0.1 | RP | Severely reduced | Severely reduced |
C | M | 18 | Early childhood | Night blindness | 0.2; 0.1 | RP | None identifiable | None identifiable |
D | M | 50 | Early childhood | Night blindness | | RP | N/A | N/A |
E | F | 7 | 7 y | Poor vision | 0.2; 0.2 | CORD | Normal | Severely reduced |
F | M | 24 | Early childhood | Night blindness | 0.07; 0.4 | RP | None identifiable | None identifiable |
G | F | 62 | Early childhood | Night blindness | | RP | N/A | N/A |
H | F | 39 | Early childhood | Night blindness | | RP | None identifiable | None identifiable |
Unaffected family members | | | | | | | | |
A-II5 | M | 65 | — | No | 0.8; 0.8 | Normal | N/A | N/A |
A-II6 | F | 56 | — | No | 0.9; 0.9 | Normal | Normal | Normal |
A-III9 | M | 46 | — | No | 1.0; 1.0 | Normal | Normal | Normal |
B-I1 | F | 40 | — | No | 1.0; 1.0 | Normal | N/A | N/A |
C-II1 | F | 26 | — | No | 1.0; 1.0 | Normal | Normal | Normal |
Control subjects | | | | | | | | |
C1 | M | 32 | — | No | 1.5; 1.5 | Normal | N/A | N/A |
C2 | F | 40 | — | No | 1.5; 1.5 | Normal | N/A | N/A |
C3 | M | 33 | — | No | 1.5; 1.5 | Normal | N/A | N/A |
C4 | M | 59 | — | No | 0.6; 1.0 | Normal | N/A | N/A |
C5 | M | 66 | — | No | 0.7; 1.0 | Normal | N/A | N/A |
C6 | F | 39 | — | No | 1.2; 1.2 | Normal | N/A | N/A |
C7 | M | 60 | — | No | 1.0; 1.0 | Normal | N/A | N/A |
C8 | F | 44 | — | No | 0.5; 0.6 | Normal | N/A | N/A |
| F | 17 | — | No | 0.7; 0.7 | Normal | N/A | N/A |
LHON1 | M | 20 | 20 y | Reduced vision | 0.1; 0.1 | LHON | N/A | N/A |
LHON2 | M | 11 | 11 y | Reduced vision | 0.2; 0.15 | LHON | N/A | N/A |
LHON3 | M | 18 | 18 y | Reduced vision | 0.1; 0.2 | LHON | N/A | N/A |
LHON4 | M | 15 | 15 y | Reduced vision | 0.1; 0.1 | LHON | N/A | N/A |
Fundus of six individuals with the 208delG mutation. (a), (b), (c): II:6, IV:4, and III:9, respectively from family A. (d): II:1 from family B. (e) and (f): II:1 and II:2 from family C. Each of the six had heterozygous 208delG mutation in FSCN2. Of the six, three on the left
column did not have retinal degeneration. The other three on the right column had LCA (b), CORD (d), or RP (f), respectively. The fundus photo of f (individual II2 of family C) demonstrated pale disc, attenuation of retinal artery, and bone spicule pigmentation although
it is of low quality (from old archive file).
The authors thank all patients and family members for their participation.
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