0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Investigation |

Expanding the Clinical Phenotype Associated With ELOVL4 Mutation Study of a Large French-Canadian Family With Autosomal Dominant Spinocerebellar Ataxia and Erythrokeratodermia FREE

Maxime Cadieux-Dion, BSc1; Maude Turcotte-Gauthier, MSc1; Anne Noreau, MSc2; Caroline Martin, BSc1; Caroline Meloche, MSc1; Micheline Gravel, BSc1; Christian Allen Drouin, MD3; Guy A. Rouleau, MD, PhD, FRCPC2; Dang Khoa Nguyen, MD, PhD, FRCPC1; Patrick Cossette, MD, PhD, FRCPC1
[+] Author Affiliations
1Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Notre Dame Hospital, University of Montreal, Montreal, Quebec, Canada
2Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada
3Department of Dermatology, Grand Portage Hospital, Rivière du Loup, Quebec, Canada
JAMA Neurol. 2014;71(4):470-475. doi:10.1001/jamaneurol.2013.6337.
Text Size: A A A
Published online

Importance  The autosomal dominant spinocerebellar ataxias (SCAs) are a complex group of neurodegenerative disorders with significant genetic heterogeneity. Despite the identification of 20 SCA genes, the cause of the disorder in a significant proportion of families with SCA remains unexplained. In 1972, a French-Canadian family segregating a combination of SCA and erythrokeratodermia variabilis (EKV) in an autosomal dominant fashion was described.

Objective  To map and identify the causative gene in this large family with SCA and EKV using a combination of linkage analysis and whole-exome sequencing.

Design, Setting, and Participants  A total of 32 individuals from the family have undergone complete neurologic and dermatologic examinations.

Main Outcomes and Measures  Mutations in ELOVL4 have been reported in families with macular degeneration. Recently, homozygous mutations were found in patients with ichthyosis, spastic paraplegia, and severe neurodevelopmental defects. In the present study, we report on a heterozygote mutation in ELOVL4 in affected individuals from the family with SCA and EKV. The mutation segregates with a milder phenotype consisting of early-onset patches of erythema and hyperkeratosis, as well as SCA manifesting in the fourth or fifth decade of life.

Results  We describe the mapping and the identification of a c.504G>C transversion in ELOVL4 resulting in the p.L168F substitution. We also provide clinical characterization of the phenotypes in 19 mutation carriers.

Conclusions and Relevance  We report, to our knowledge, the first mutation in ELOVL4 that is associated with SCA and EKV. This gene encodes a member of the elongase family, which is responsible for the elongation of very long-chain fatty acids (at least 26 carbons). These fatty acids participate in a wide variety of physiological functions, including skin barrier formation and peroxisome β-oxidation. Overall, these results provide additional insight into the pathogenesis of these complex neurodegenerative disorders.

Figures in this Article

The autosomal dominant spinocerebellar ataxias (SCAs) are a complex group of neurodegenerative disorders characterized by progressive cerebellar ataxia of gait and the extremities variably associated with other neurologic signs. The prevalence of inherited ataxias is approximately 3 to 6 individuals per 100 000 people in the general population.1 At least 32 distinct loci have been identified for SCAs and, of these, 20 SCA genes have so far been documented. Nucleotide repeat expansions, genomic deletions and duplications, and point mutations have been associated2 with the disease, suggesting genetic heterogeneity of the pathogenic mechanisms. To date, a significant proportion of SCA in families remains genetically unexplained.

In 1972, a unique French-Canadian (FC) family segregating a combination of ataxia and skin lesions in an autosomal dominant fashion (SCA34, OMIM 133190) was reported by Giroux and Barbeau.3 The skin lesions were typical of erythrokeratodermia variabilis (EKV, OMIM 133200), a heterogeneous group of diseases characterized by erythematous lesions and hyperkeratosis. The pure form of EKV has been associated4 with mutations in 2 connexin genes, GJB3 and GJB4, on chromosome 1p35.1, but additional genes causing EKV remain to be identified. There is growing evidence that mutations in genes causing keratodermias also predispose people to various neurologic disorders, including deafness, peripheral neuropathy, and mental retardation.5,6 Interestingly, a mutation in the gene GJB1 has recently been associated7 with X-linked ataxia with peripheral nervous system features. However, to our knowledge, neither skin lesions nor keratodermia have been reported in families with SCA except for the FC family described by Giroux and Barbeau.3,8,9

Preliminary studies8 with several affected individuals from this family have suggested linkage at the EKV1/EKV2 locus, but no mutation has been identified. We describe in the present study the mapping of the gene for this unique syndrome on chromosome 6p12.3-q16.1, as well as the identification of a p.L168F (c.504G>C) mutation in the gene ELOVL4 (RefSeq NM_022726) by using whole-exome sequencing. The p.L168F mutation segregates well with the disease, and we provide detailed clinical characterization of 19 mutation-positive individuals from this family.

Participants

We investigated an FC kindred presenting a combination of erythrokeratodermia with ataxia. The description of clinical phenotypes of the early generations of the family has been previously described.3 We collected genomic DNA from 32 individuals of this family. These individuals underwent complete neurologic and dermatologic examinations. Measurement of long-chain fatty acids (C22, C24, and C26) was performed on 2 affected individuals (V-3 and V-24 [Figure 1A]) (Centre Hospitalier Universitaire de Sherbrooke). An additional cohort of 95 patients with unexplained SCA was used for gene screening. After participants provided written informed consent, genomic DNA was extracted from blood samples using standard protocols. This project was approved by the research ethics committee of the Centre Hospitalier de l’Université de Montréal. The participants received no financial compensation.

Place holder to copy figure label and caption
Figure 1.
Identification and Characterization of a Missense Mutation in ELOVL4

A, Pedigree of the French-Canadian family in whom the mutation was found. Patients V-3, V-5, and V-24 were used for exome sequencing. Among samples in which DNA was available, we identified individuals with (+) or without (−) a mutation in ELOVL4. For VI-7, there were 2 individuals of different sex with the same mutation status. EKV indicates erythrokeratodermia variabilis. B, In affected individuals, the c.504G>C transversion was observed, resulting in the p.L168F substitution. Asterisks indicate which nucleotide (upper portion) and which amino acid (lower portion) were implicated in the mutation. C, The protein is composed of 5 transmembrane (TM) domains (gray), a histidine cluster dideoxy binding motif (orange), and an endoplasmic reticulum retention signal (green). The mutation (red F) involves a well-conserved residue (boxed) and is located within the third TM domain. The letters represent the single-letter codes for amino acids.

Graphic Jump Location
Genotyping and Linkage Analysis

A genome-wide scan of the FC family was performed at deCODE genetics using 524 evenly distributed microsatellite markers covering the whole genome at intervals of approximately 8 centimorgans. Microsatellite markers used to refine the disease locus were genotyped by polymerase chain reaction incorporating primers with fluorescently labeled M13mp18 sequence tails (primer and polymerase chain reaction details available on request), as described elsewhere.10 We calculated pairwise logarithm of odds scores (MLINK program, version 5.1; LINKAGE; http://www.jurgott.org/linkage/LinkagePC.html) under the assumption of an autosomal dominant mode of inheritance, a disease frequency of 1:10 000, 90% penetrance, 1/10 000 of phenocopy, and allele isofrequency. We also performed a multipoint linkage analysis using the same variables with a different program (SimWalk, version 2.91; University of California, Los Angeles, Human Genetics; http://www.genetics.ucla.edu/software/).

Copy Number Variation

A fine-tiling array comparative genomic hybridization, covering the entire chromosome 6, was performed on one affected individual from the large FC family (participant IV-16). We used 3 different arrays with a probe density of 1/4000 base pair (bp), 1/8000 bp, and 1/20 000 bp (NimbleGen).11 We also performed a whole-genome genotyping and copy number variation analysis (human 610-Quad BeadChip; Illumina).12,13

Exome Sequencing and Validation of Variants

Three affected individuals (V-3, V-5, and V-24) from distinct branches of the family (Figure 1A) were selected for exome sequencing. Genomic DNA (5 μg) was fragmented and enriched (SureSelect Human All Exon V4 kit; Agilent Technologies). The prepared library was sequenced with paired-end reads (HiSeq 2000; Illumina). The reads were mapped against the human genome (hg19) (Burrows-Wheeler Aligner; http://bio-bwa.sourceforge.net). Reads with a unique mapping location were kept for downstream analysis. Gene Analysis Tool Kit (Broad Institute; http://www.broadinstitute.org/gatk/) and ANNOVAR (http://www.openbioinformatics.org/annovar/) were used for the calling of single-nucleotide variations, small insertions, and small deletions (indels). Called variants were filtered against dbSNP132 as well as individuals from our in-house exome database. For the validation of next-generation sequencing variants, primers were designed with the software Primer 3 (http://bioinfo.ut.ee/primer3-0.4.0/) to amplify the coding region encompassing the putative variation.

Sequencing of ELOVL4 in Patients With SCA

We sequenced all of the coding exons as well as 20 bp of the exon-intron boundaries of the gene ELOVL4 in 95 patients with SCA. Polymerase chain reaction primers were designed using Primer 3. The primer sequences and polymerase chain reaction conditions are available on request. The amplicons were then sequenced (ABI 3730xl DNA Analyzer; Life Technologies) and analyzed (Mutation Surveyor, version 3.0; Softgenetics).

Linkage Analysis and Exome Sequencing

We first excluded linkage at the EKV1/EKV2 and MEDNIK loci in the FC family (data not shown). Genome-wide linkage analysis revealed 3 positive chromosomal regions with a logarithm of odds score superior to 1.5 on chromosomes 1, 6, and 7 (data not shown). Further analysis with additional markers and additional affected individuals confirmed linkage to chromosome 6, with a maximum logarithm of odds score of Z = 5.33 at θ = 0 found for marker D6S452. Haplotype analysis allowed the identification of a candidate locus of 46.8 megabases between markers D6S459 and D6S417 at chromosome 6p12.3-q16.1 (Supplement [eFigure]). We also performed comparative genomic hybridization analysis that did not reveal significant copy number variations in this candidate gene region. In turn, whole-exome sequencing allowed us to identify a p.L168F (c.504G>C) mutation in ELOVL4 (Figure 1B) (RefSeq NM_022726), a gene located in the candidate interval (Supplement [eTable 1]). This genetic variation was found in the 3 affected individuals (V-3, V-5, and V-24). Sanger sequencing confirmed that this genetic variation segregated with the disease haplotype in 19 individuals. This mutation was not found in 189 additional control individuals, nor was it found in public databases, such as 1000 Genomes (http://browser.1000genomes.org) and Exome Variant Server (http://evs.gs.washington.edu/EVS). Screening of 95 additional patients with SCA failed to identify additional mutations in ELOVL4.

Clinical Manifestations of Mutation Carriers

The summary of the detailed clinical examination performed on 19 mutation carriers from the FC family is reported in the Supplement (eTable 2). Erythrokeratodermia variabilis (n = 3), ataxia (n = 1), or a combination of both phenotypes (n = 11) was found in the mutation carriers; the others were unaffected. As previously described,3 2 types of skin lesions can be distinguished. First, erythematous and hyperkeratotic plaques are most commonly observed over the dorsal aspects of the hands and feet, the elbows, the ankles, and the external ears. The hyperkeratosis usually is more prominent than the erythema, and a fine scaling is observed over those persistent plaques (Figure 2A). Second, transient, figurate, and erythematous patches are observed over the legs, thighs, and buttocks (Figure 2B). Both types of lesions are usually symmetrically distributed and vary in severity among patients, becoming worse in winter and improving with the use of emollients. The onset is in early infancy and, in most cases, the lesions disappear after the patient is 25 years of age. In all patients, hair, nails, and scalp were normal. No hearing impairment was detected, and cognition appeared normal. The onset of gait ataxia usually occurred in the fourth or fifth decade of life (mean, 51 years), but it could occur as early as the third decade in some patients. The progression of gait disturbance is very slow. Patients may need to use a cane after 10 years of disease progression. The affected individuals in the present study usually required a walker in their mid-60s or 70s, although other medical conditions may have contributed to the gait disturbance (eg, aortic aneurysm, metastatic breast cancer, chronic alcohol consumption, and severe emphysema) (Supplement [eTable 2]). Magnetic resonance imaging conducted in 7 individuals with mild or moderate ataxia showed cerebellar and pontine atrophy (Figure 2C). In these affected individuals, the atrophy was more severe in the vermis than in the cerebellar hemispheres. In turn, 2 individuals with EKV lesions without ataxia had normal magnetic resonance imaging findings. Individual V-24, who had EKV lesions and very mild ataxia, also exhibited cerebellar hypometabolism on 18F-fluorodeoxyglucose–positron emission tomography (Figure 2D). An electromyogram obtained in 8 affected family members, including 1 study participant (13%) with EKV lesions only, disclosed mild axonal peripheral neuropathy in 4 of the 8 individuals (50%) (Supplement [eTable 2]). The mutation was also found in 4 individuals (V-16, VI-4, VI-6, and VI-11; 21%) (Figure 1A) without any neurologic manifestations or skin lesions. Lipid analysis from whole-blood samples of 2 affected individuals (V-3 and V-24) did not reveal abnormal levels of long-chain fatty acids (C22, C24, and C26). However, the linoleic acid level was slightly above the reference range.

Place holder to copy figure label and caption
Figure 2.
Clinical Phenotype of the French-Canadian Family

A, Erythematous and hyperkeratotic plaque covered with fine scales over the heel and ankle. B, Patches of erythema over the thigh. The lesions are typically symmetrical. C, Magnetic resonance image showing severe atrophy of the cerebellum and the pons (participant V-8). D, Brain fluorodeoxyglucose positron emission tomography showing cerebellar hypometabolism in an individual (participant V-24) with very mild ataxia but without cerebellar atrophy, compatible with an earlier stage of the disease.

Graphic Jump Location

We evaluated a p.L168F mutation in ELOVL4 segregating with SCA and EKV in a large FC family by using a combination of genome scan and whole-exome sequencing. Based on the strong linkage found on chromosome 6p12.3-q16.1, we filtered for genetic variants and found the ELOVL4 mutation as the only coding genetic variation in 3 affected individuals who were tested. The mutation segregates well with the disease phenotype and was not found in control individuals or in public databases. Moreover, ELOVL4 is a very good candidate gene because mutations, in both human and animal models, have been associated14,15 with skin defects and neurologic impairments. Taken together, our data are consistent with the identification of ELOVL4 as the causative gene for the EKV and SCA in this FC family.

The ELOVL4 gene encodes for a member of the elongase family and is involved in the elongation of very long-chain fatty acids. The Elovl4 protein is expressed in the retina, brain, testes, and skin.16 As a 314–amino acid protein, Elovl4 is predicted to have 5 transmembrane segments, a histamine cluster dideoxy binding motif, and a dilysine endoplasmic reticulum retention motif (Figure 1C).17 Biochemical analysis18 revealed its implication in the biosynthesis of very long-chain fatty acids, specifically elongating both saturated and unsaturated C26 to C28 products and C28 to products of 30 to 38 carbons. Very long-chain fatty acids participate in a wide variety of physiological functions, including skin barrier formation14 and peroxisome β-oxidation, which is known to be involved in several neurodevelopmental disorders.19 After differentiation of the keratinocytes, different layers of the epidermis are developed, including the stratum corneum.20 This outermost layer of the epidermis acts as a transepidermal barrier that prevents dehydration. It is mainly composed of ceramides containing ω-hydroxy long-chain fatty acids. Interestingly, knockout mice for Elovl4 die several hours after birth and show severe skin atrophy. They also display reduced body movement, suggesting abnormal neurologic behavior.21

The gene ELOVL4 has been associated2224 with a juvenile form of macular degeneration: Stargardt disease type 3 (STGD3; OMIM 600110). The disease segregates in an autosomal dominant pattern of inheritance, and patients heterozygous for these mutations show progressive macular degeneration and loss of central vision. Three pathogenic variants have been reported,25 resulting in a truncated protein lacking the dilysine endoplasmic reticulum retention motif. In vitro studies17 have shown that mutant proteins are mislocalized and exert a dominant negative effect on the wild-type protein to form aggresomes of both normal and aberrant Elovl4. Interestingly, 2 additional homozygous mutations were found in patients with ichthyosis and severe neurologic disturbances, such as spastic paraplegia and neurodevelopmental defects.14 The p.L168F missense mutation described in the present study is located within the third transmembrane domain (Figure 1C) and is predicted to be pathogenic by Mutation Taster (http:\\www.mutationtaster.org) and PROVEAN,26 and possibly damaging by Polyphen2.27 Further characterization of the mutation will be necessary to understand the role of the mutation in the disease. It is possible that the localization of the mutation in the FC family in a different domain of the protein could be responsible for the phenotypic differences observed in patients with Stargardt disease type 3.

In the present study, a total of 19 ELOVL4 p.L168F mutation carriers were identified for whom we obtained detailed neurologic and physical examination results (Supplement [eTable 2]). Most (11 [58%]) individuals bearing the p.L168F mutation exhibited a combination of EKV and ataxia. Other mutation carriers (3 [16%]) showed only EKV, most likely because they were younger (aged 36, 33, and 44 years). One (5%) mutation carrier showed cerebellar ataxia at 55 years, without apparent skin lesions. The EKV lesions are usually apparent during childhood, may be minimized by hydrating lotions, and in some instances disappear over time. Therefore, we cannot exclude that EKV has been overlooked in this individual despite careful assessment. Alternatively, incomplete penetrance for the skin phenotype may exist. Finally, we have identified asymptomatic mutation carriers (4 [21%]), suggesting incomplete penetrance for EKV (Supplement [eTable 2]). Because of their relatively young age and considering the late-onset disease course of the ataxic features, it is possible that these carriers may eventually become symptomatic.

The heterogeneity of clinical manifestations associated with mutations in ELOVL4 in humans is intriguing. Although originally described in macular degeneration (Stargard disease type 3) without skin lesions, homozygous mutations have been associated14 with ichthyosis, encephalopathy, and epilepsy, without macular degeneration. In our FC family, EKV lesions were reminiscent of ichthyosis, but we found no clinical evidence of macular degeneration. In Elovl4 knockout mice, skin lesions appear to be a common feature, but depletion of very long-chain polyunsaturated fatty acids in the retina does not seem to affect visual function.28 These observations are consistent with other EKV and ichthyosis genes that are associated with heterogeneous neurologic manifestations.4,6

To our knowledge, we have described, for the first time, a missense mutation in the gene ELOVL4 associated with SCA as well as EKV. Finding additional mutations in ELOVL4 in other SCA families, as well as functional characterization of these mutations, should provide additional insights on disease pathogenesis.

Accepted for Publication: December 26, 2013.

Corresponding Author: Patrick Cossette, MD, PhD, FRCPC, CHUM-Notre Dame Hospital, 1560 Sherbrooke Est, Montreal, QC H2L 4M1, Canada (patrick.cossette@umontreal.ca).

Published Online: February 24, 2014. doi:10.1001/jamaneurol.2013.6337.

Author Contributions: Dr Cossette had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Cadieux-Dion, Turcotte-Gauthier, Rouleau, Cossette.

Acquisition of data: Cadieux-Dion, Turcotte-Gauthier, Noreau, Martin, Meloche, Gravel, Drouin, Nguyen.

Analysis and interpretation of data: Cadieux-Dion, Turcotte-Gauthier, Martin, Drouin, Nguyen.

Drafting of the manuscript: Cadieux-Dion, Turcotte-Gauthier, Nguyen, Cossette.

Critical revision of the manuscript for important intellectual content: Noreau, Martin, Meloche, Gravel, Drouin, Rouleau.

Obtained funding: Rouleau, Cossette.

Administrative, technical, or material support: Meloche, Gravel.

Study supervision: Nguyen, Cossette.

Conflict of Interest Disclosures: None reported.

Funding/Support: Mr Cadieux-Dion is supported by the Réseau de Médecine Génétique Appliquée and La Fondation GO. Ms Martin and Dr Nguyen are supported by the Fonds de Recherche du Québec–Santé. Drs Rouleau and Cossette are supported by the Canadian Institutes of Health Research. Ms Noreau received the Doctoral Award–Frederick Banting and Charles Best Graduate Scholarship from the Canadian Institutes of Health Research.

Role of the Sponsor: The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We thank the FC family for their participation in the study. Yves Léo Lamarre, MD, Department of Neurology, Notre Dame Hospital, Montreal, reviewed all nerve conduction studies and electromyographic recordings.

Cagnoli  C, Mariotti  C, Taroni  F,  et al.  SCA28, a novel form of autosomal dominant cerebellar ataxia on chromosome 18p11.22-q11.2. Brain. 2006;129(pt 1):235-242.
PubMed
Lee  YC, Durr  A, Majczenko  K,  et al.  Mutations in KCND3 cause spinocerebellar ataxia type 22. Ann Neurol. 2012;72(6):859-869.
PubMed   |  Link to Article
Giroux  JM, Barbeau  A.  Erythrokeratodermia with ataxia. Arch Dermatol. 1972;106(2):183-188.
PubMed   |  Link to Article
Scott  CA, Tattersall  D, O’Toole  EA, Kelsell  DP.  Connexins in epidermal homeostasis and skin disease. Biochim Biophys Acta. 2012;1818(8):1952-1961.
PubMed   |  Link to Article
López-Bigas  N, Olivé  M, Rabionet  R,  et al.  Connexin 31 (GJB3) is expressed in the peripheral and auditory nerves and causes neuropathy and hearing impairment. Hum Mol Genet. 2001;10(9):947-952.
PubMed   |  Link to Article
Montpetit  A, Côté  S, Brustein  E,  et al.  Disruption of AP1S1, causing a novel neurocutaneous syndrome, perturbs development of the skin and spinal cord. PLoS Genet. 2008;4(12):e1000296. doi:10.1371/journal.pgen.1000296.
PubMed   |  Link to Article
Caramins  M, Colebatch  JG, Bainbridge  MN,  et al.  Exome sequencing identification of a GJB1 missense mutation in a kindred with X-linked spinocerebellar ataxia (SCA-X1). Hum Mol Genet. 2013;22(21):4329-4338.
PubMed   |  Link to Article
Richard  G, Lin  JP, Smith  L,  et al.  Linkage studies in erythrokeratodermias: fine mapping, genetic heterogeneity and analysis of candidate genes. J Invest Dermatol. 1997;109(5):666-671.
PubMed   |  Link to Article
Seidel  K, Siswanto  S, Brunt  ER, den Dunnen  W, Korf  HW, Rüb  U.  Brain pathology of spinocerebellar ataxias. Acta Neuropathol. 2012;124(1):1-21.
PubMed   |  Link to Article
Kinirons  P, Verlaan  DJ, Dubé  MP,  et al.  A novel locus for idiopathic generalized epilepsy in French-Canadian families maps to 10p11. Am J Med Genet A. 2008;146A(5):578-584.
PubMed   |  Link to Article
Saillour  Y, Cossée  M, Leturcq  F,  et al.  Detection of exonic copy-number changes using a highly efficient oligonucleotide-based comparative genomic hybridization-array method. Hum Mutat. 2008;29(9):1083-1090.
PubMed   |  Link to Article
van de Leemput  J, Chandran  J, Knight  MA,  et al.  Deletion at ITPR1 underlies ataxia in mice and spinocerebellar ataxia 15 in humans. PLoS Genet. 2007;3(6):e108. doi:10.1371/journal.pgen.0030108.
PubMed   |  Link to Article
Sharp  AJ, Mefford  HC, Li  K,  et al.  A recurrent 15q13.3 microdeletion syndrome associated with mental retardation and seizures. Nat Genet. 2008;40(3):322-328.
PubMed   |  Link to Article
Aldahmesh  MA, Mohamed  JY, Alkuraya  HS,  et al.  Recessive mutations in ELOVL4 cause ichthyosis, intellectual disability, and spastic quadriplegia. Am J Hum Genet. 2011;89(6):745-750.
PubMed   |  Link to Article
McMahon  A, Butovich  IA, Kedzierski  W.  Epidermal expression of an Elovl4 transgene rescues neonatal lethality of homozygous Stargardt disease-3 mice. J Lipid Res. 2011;52(6):1128-1138.
PubMed   |  Link to Article
Molday  RS, Zhang  K.  Defective lipid transport and biosynthesis in recessive and dominant Stargardt macular degeneration. Prog Lipid Res. 2010;49(4):476-492.
PubMed   |  Link to Article
Grayson  C, Molday  RS.  Dominant negative mechanism underlies autosomal dominant Stargardt-like macular dystrophy linked to mutations in ELOVL4. J Biol Chem. 2005;280(37):32521-32530.
PubMed   |  Link to Article
Agbaga  MP, Brush  RS, Mandal  MN, Henry  K, Elliott  MH, Anderson  RE.  Role of Stargardt-3 macular dystrophy protein (ELOVL4) in the biosynthesis of very long chain fatty acids. Proc Natl Acad Sci U S A. 2008;105(35):12843-12848.
PubMed   |  Link to Article
Verheijden  S, Bottelbergs  A, Krysko  O,  et al.  Peroxisomal multifunctional protein-2 deficiency causes neuroinflammation and degeneration of Purkinje cells independent of very long chain fatty acid accumulation. Neurobiol Dis. 2013;58:258-269.
PubMed   |  Link to Article
Rissmann  R, Groenink  HW, Weerheim  AM, Hoath  SB, Ponec  M, Bouwstra  JA.  New insights into ultrastructure, lipid composition and organization of vernix caseosa. J Invest Dermatol. 2006;126(8):1823-1833.
PubMed   |  Link to Article
Li  W, Sandhoff  R, Kono  M,  et al.  Depletion of ceramides with very long chain fatty acids causes defective skin permeability barrier function, and neonatal lethality in ELOVL4 deficient mice. Int J Biol Sci. 2007;3(2):120-128.
PubMed   |  Link to Article
Maugeri  A, Meire  F, Hoyng  CB,  et al.  A novel mutation in the ELOVL4 gene causes autosomal dominant Stargardt-like macular dystrophy. Invest Ophthalmol Vis Sci. 2004;45(12):4263-4267.
PubMed   |  Link to Article
Bernstein  PS, Tammur  J, Singh  N,  et al.  Diverse macular dystrophy phenotype caused by a novel complex mutation in the ELOVL4 gene. Invest Ophthalmol Vis Sci. 2001;42(13):3331-3336.
PubMed
Zhang  K, Kniazeva  M, Han  M,  et al.  A 5-bp deletion in ELOVL4 is associated with two related forms of autosomal dominant macular dystrophy. Nat Genet. 2001;7(1)89-93.
PubMed
Harkewicz  R, Du  H, Tong  Z,  et al.  Essential role of ELOVL4 protein in very long chain fatty acid synthesis and retinal function. J Biol Chem. 2012;287(14):11469-11480.
PubMed   |  Link to Article
Choi  Y, Sims  GE, Murphy  S, Miller  JR, Chan  AP.  Predicting the functional effect of amino acid substitutions and indels. PLoS One. 2012;7(10):e46688. doi:10.1371/journal.pone.0046688.
PubMed   |  Link to Article
Adzhubei  IA, Schmidt  S, Peshkin  L,  et al.  A method and server for predicting damaging missense mutations. Nat Methods. 2010;7(4):248-249.
PubMed   |  Link to Article
Barabas  P, Liu  A, Xing  W,  et al.  Role of ELOVL4 and very long-chain polyunsaturated fatty acids in mouse models of Stargardt type 3 retinal degeneration. Proc Natl Acad Sci U S A. 2013;110(13):5181-5186.
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.
Identification and Characterization of a Missense Mutation in ELOVL4

A, Pedigree of the French-Canadian family in whom the mutation was found. Patients V-3, V-5, and V-24 were used for exome sequencing. Among samples in which DNA was available, we identified individuals with (+) or without (−) a mutation in ELOVL4. For VI-7, there were 2 individuals of different sex with the same mutation status. EKV indicates erythrokeratodermia variabilis. B, In affected individuals, the c.504G>C transversion was observed, resulting in the p.L168F substitution. Asterisks indicate which nucleotide (upper portion) and which amino acid (lower portion) were implicated in the mutation. C, The protein is composed of 5 transmembrane (TM) domains (gray), a histidine cluster dideoxy binding motif (orange), and an endoplasmic reticulum retention signal (green). The mutation (red F) involves a well-conserved residue (boxed) and is located within the third TM domain. The letters represent the single-letter codes for amino acids.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.
Clinical Phenotype of the French-Canadian Family

A, Erythematous and hyperkeratotic plaque covered with fine scales over the heel and ankle. B, Patches of erythema over the thigh. The lesions are typically symmetrical. C, Magnetic resonance image showing severe atrophy of the cerebellum and the pons (participant V-8). D, Brain fluorodeoxyglucose positron emission tomography showing cerebellar hypometabolism in an individual (participant V-24) with very mild ataxia but without cerebellar atrophy, compatible with an earlier stage of the disease.

Graphic Jump Location

Tables

References

Cagnoli  C, Mariotti  C, Taroni  F,  et al.  SCA28, a novel form of autosomal dominant cerebellar ataxia on chromosome 18p11.22-q11.2. Brain. 2006;129(pt 1):235-242.
PubMed
Lee  YC, Durr  A, Majczenko  K,  et al.  Mutations in KCND3 cause spinocerebellar ataxia type 22. Ann Neurol. 2012;72(6):859-869.
PubMed   |  Link to Article
Giroux  JM, Barbeau  A.  Erythrokeratodermia with ataxia. Arch Dermatol. 1972;106(2):183-188.
PubMed   |  Link to Article
Scott  CA, Tattersall  D, O’Toole  EA, Kelsell  DP.  Connexins in epidermal homeostasis and skin disease. Biochim Biophys Acta. 2012;1818(8):1952-1961.
PubMed   |  Link to Article
López-Bigas  N, Olivé  M, Rabionet  R,  et al.  Connexin 31 (GJB3) is expressed in the peripheral and auditory nerves and causes neuropathy and hearing impairment. Hum Mol Genet. 2001;10(9):947-952.
PubMed   |  Link to Article
Montpetit  A, Côté  S, Brustein  E,  et al.  Disruption of AP1S1, causing a novel neurocutaneous syndrome, perturbs development of the skin and spinal cord. PLoS Genet. 2008;4(12):e1000296. doi:10.1371/journal.pgen.1000296.
PubMed   |  Link to Article
Caramins  M, Colebatch  JG, Bainbridge  MN,  et al.  Exome sequencing identification of a GJB1 missense mutation in a kindred with X-linked spinocerebellar ataxia (SCA-X1). Hum Mol Genet. 2013;22(21):4329-4338.
PubMed   |  Link to Article
Richard  G, Lin  JP, Smith  L,  et al.  Linkage studies in erythrokeratodermias: fine mapping, genetic heterogeneity and analysis of candidate genes. J Invest Dermatol. 1997;109(5):666-671.
PubMed   |  Link to Article
Seidel  K, Siswanto  S, Brunt  ER, den Dunnen  W, Korf  HW, Rüb  U.  Brain pathology of spinocerebellar ataxias. Acta Neuropathol. 2012;124(1):1-21.
PubMed   |  Link to Article
Kinirons  P, Verlaan  DJ, Dubé  MP,  et al.  A novel locus for idiopathic generalized epilepsy in French-Canadian families maps to 10p11. Am J Med Genet A. 2008;146A(5):578-584.
PubMed   |  Link to Article
Saillour  Y, Cossée  M, Leturcq  F,  et al.  Detection of exonic copy-number changes using a highly efficient oligonucleotide-based comparative genomic hybridization-array method. Hum Mutat. 2008;29(9):1083-1090.
PubMed   |  Link to Article
van de Leemput  J, Chandran  J, Knight  MA,  et al.  Deletion at ITPR1 underlies ataxia in mice and spinocerebellar ataxia 15 in humans. PLoS Genet. 2007;3(6):e108. doi:10.1371/journal.pgen.0030108.
PubMed   |  Link to Article
Sharp  AJ, Mefford  HC, Li  K,  et al.  A recurrent 15q13.3 microdeletion syndrome associated with mental retardation and seizures. Nat Genet. 2008;40(3):322-328.
PubMed   |  Link to Article
Aldahmesh  MA, Mohamed  JY, Alkuraya  HS,  et al.  Recessive mutations in ELOVL4 cause ichthyosis, intellectual disability, and spastic quadriplegia. Am J Hum Genet. 2011;89(6):745-750.
PubMed   |  Link to Article
McMahon  A, Butovich  IA, Kedzierski  W.  Epidermal expression of an Elovl4 transgene rescues neonatal lethality of homozygous Stargardt disease-3 mice. J Lipid Res. 2011;52(6):1128-1138.
PubMed   |  Link to Article
Molday  RS, Zhang  K.  Defective lipid transport and biosynthesis in recessive and dominant Stargardt macular degeneration. Prog Lipid Res. 2010;49(4):476-492.
PubMed   |  Link to Article
Grayson  C, Molday  RS.  Dominant negative mechanism underlies autosomal dominant Stargardt-like macular dystrophy linked to mutations in ELOVL4. J Biol Chem. 2005;280(37):32521-32530.
PubMed   |  Link to Article
Agbaga  MP, Brush  RS, Mandal  MN, Henry  K, Elliott  MH, Anderson  RE.  Role of Stargardt-3 macular dystrophy protein (ELOVL4) in the biosynthesis of very long chain fatty acids. Proc Natl Acad Sci U S A. 2008;105(35):12843-12848.
PubMed   |  Link to Article
Verheijden  S, Bottelbergs  A, Krysko  O,  et al.  Peroxisomal multifunctional protein-2 deficiency causes neuroinflammation and degeneration of Purkinje cells independent of very long chain fatty acid accumulation. Neurobiol Dis. 2013;58:258-269.
PubMed   |  Link to Article
Rissmann  R, Groenink  HW, Weerheim  AM, Hoath  SB, Ponec  M, Bouwstra  JA.  New insights into ultrastructure, lipid composition and organization of vernix caseosa. J Invest Dermatol. 2006;126(8):1823-1833.
PubMed   |  Link to Article
Li  W, Sandhoff  R, Kono  M,  et al.  Depletion of ceramides with very long chain fatty acids causes defective skin permeability barrier function, and neonatal lethality in ELOVL4 deficient mice. Int J Biol Sci. 2007;3(2):120-128.
PubMed   |  Link to Article
Maugeri  A, Meire  F, Hoyng  CB,  et al.  A novel mutation in the ELOVL4 gene causes autosomal dominant Stargardt-like macular dystrophy. Invest Ophthalmol Vis Sci. 2004;45(12):4263-4267.
PubMed   |  Link to Article
Bernstein  PS, Tammur  J, Singh  N,  et al.  Diverse macular dystrophy phenotype caused by a novel complex mutation in the ELOVL4 gene. Invest Ophthalmol Vis Sci. 2001;42(13):3331-3336.
PubMed
Zhang  K, Kniazeva  M, Han  M,  et al.  A 5-bp deletion in ELOVL4 is associated with two related forms of autosomal dominant macular dystrophy. Nat Genet. 2001;7(1)89-93.
PubMed
Harkewicz  R, Du  H, Tong  Z,  et al.  Essential role of ELOVL4 protein in very long chain fatty acid synthesis and retinal function. J Biol Chem. 2012;287(14):11469-11480.
PubMed   |  Link to Article
Choi  Y, Sims  GE, Murphy  S, Miller  JR, Chan  AP.  Predicting the functional effect of amino acid substitutions and indels. PLoS One. 2012;7(10):e46688. doi:10.1371/journal.pone.0046688.
PubMed   |  Link to Article
Adzhubei  IA, Schmidt  S, Peshkin  L,  et al.  A method and server for predicting damaging missense mutations. Nat Methods. 2010;7(4):248-249.
PubMed   |  Link to Article
Barabas  P, Liu  A, Xing  W,  et al.  Role of ELOVL4 and very long-chain polyunsaturated fatty acids in mouse models of Stargardt type 3 retinal degeneration. Proc Natl Acad Sci U S A. 2013;110(13):5181-5186.
PubMed   |  Link to Article

Correspondence

CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Please click the checkbox indicating that you have read the full article in order to submit your answers.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.

Multimedia

Supplement.

eFigure. The large French-Canadian family with ataxia and erythrokeratodermia maps to chromosome 6p12.3-q16.1

eTable1. Detailed alignment statistics of the next generation sequencing data

eTable 2. Clinical characterization of individuals with the p.L168F mutation

Supplemental Content

Some tools below are only available to our subscribers or users with an online account.

1,431 Views
16 Citations
×

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles
Jobs