Expanding the Clinical Phenotype Associated with ELOVL4 Mutation

Research

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

Maxime Cadieux-Dion, BSc; Maude Turcotte-Gauthier, MSc; Anne Noreau, MSc; Caroline Martin, BSc; Caroline Meloche, MSc; Micheline Gravel, BSc; Christian Allen Drouin, MD; Guy A. Rouleau, MD, PhD, FRCPC; Dang Khoa Nguyen, MD, PhD, FRCPC; Patrick Cossette, MD, PhD, FRCPC

Supplemental content at IMPORTANCE The autosomal dominant spinocerebellar ataxias (SCAs) are a complex group of jamaneurology.com 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 Author Affiliations: Centre de that is associated with SCA and EKV. This gene encodes a member of the elongase family, Recherche du Centre Hospitalier de which is responsible for the elongation of very long-chain fatty acids (at least 26 carbons). l’Université de Montréal, Notre Dame These fatty acids participate in a wide variety of physiological functions, including skin barrier Hospital, University of Montreal, formation and peroxisome β-oxidation. Overall, these results provide additional insight into Montreal, Quebec, Canada (Cadieux-Dion, Turcotte-Gauthier, the pathogenesis of these complex neurodegenerative disorders. Martin, Meloche, Gravel, Nguyen, Cossette); Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada (Noreau, Rouleau); Department of Dermatology, Grand Portage Hospital, Rivière du Loup, Quebec, Canada (Drouin). Corresponding Author: Patrick Cossette, MD, PhD, FRCPC, CHUM-Notre Dame Hospital, 1560 Sherbrooke Est, Montreal, QC H2L JAMA Neurol. 2014;71(4):470-475. doi:10.1001/jamaneurol.2013.6337 4M1, Canada (patrick.cossette Published online February 24, 2014. @umontreal.ca).

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he autosomal dominant spinocerebellar ataxias (SCAs) blood samples using standard protocols. This project was are a complex group of neurodegenerative disorders approved by the research ethics committee of the Centre T characterized by progressive cerebellar ataxia of gait and Hospitalier de l’Université de Montréal. The participants the extremities variably associated with other neurologic signs. received no financial compensation. The prevalence of inherited ataxias is approximately 3 to 6 individuals per 100 000 people in the general population.1 At least Genotyping and Linkage Analysis 32 distinct loci have been identified for SCAs and, of these, 20 A genome-wide scan of the FC family was performed at SCA genes have so far been documented. Nucleotide repeat ex- deCODE genetics using 524 evenly distributed microsatellite pansions, genomic deletions and duplications, and point mu- markers covering the whole genome at intervals of approxi- tations have been associated2 with the disease, suggesting ge- mately 8 centimorgans. Microsatellite markers used to refine netic heterogeneity of the pathogenic mechanisms. To date, the disease locus were genotyped by polymerase chain reac- a significant proportion of SCA in families remains geneti- tion incorporating primers with fluorescently labeled M13mp18 cally unexplained. sequence tails (primer and polymerase chain reaction details In 1972, a unique French-Canadian (FC) family segregat- available on request), as described elsewhere.10 We calcu- ing a combination of ataxia and skin lesions in an autosomal lated pairwise logarithm of odds scores (MLINK program, ver- dominant fashion (SCA34, OMIM 133190) was reported by Gi- sion 5.1; LINKAGE; http://www.jurgott.org/linkage/LinkagePC roux and Barbeau.3 The skin lesions were typical of erythro- .html) under the assumption of an autosomal dominant mode keratodermia variabilis (EKV, OMIM 133200), a heteroge- of inheritance, a disease frequency of 1:10 000, 90% pen- neous group of diseases characterized by erythematous lesions etrance, 1/10 000 of phenocopy, and allele isofrequency. We and hyperkeratosis. The pure form of EKV has been associated4 also performed a multipoint linkage analysis using the same with mutations in 2 connexin genes, GJB3 and GJB4,onchro- variables with a different program (SimWalk, version 2.91; Uni- mosome 1p35.1, but additional genes causing EKV remain to versity of California, Los Angeles, Human Genetics; http://www be identified. There is growing evidence that mutations in .genetics.ucla.edu/software/). genes causing keratodermias also predispose people to vari- ous neurologic disorders, including deafness, peripheral neu- Copy Number Variation ropathy, and mental retardation.5,6 Interestingly, a mutation A fine-tiling array comparative genomic hybridization, cover- in the gene GJB1 has recently been associated7 with X-linked ing the entire chromosome 6, was performed on one affected ataxia with peripheral nervous system features. However, to individual from the large FC family (participant IV-16). We used our knowledge, neither skin lesions nor keratodermia have 3 different arrays with a probe density of 1/4000 base pair (bp), been reported in families with SCA except for the FC family 1/8000 bp, and 1/20 000 bp (NimbleGen).11 We also per- described by Giroux and Barbeau.3,8,9 formed a whole-genome genotyping and copy number varia- Preliminary studies8 with several affected individuals from tion analysis (human 610-Quad BeadChip; Illumina).12,13 this family have suggested linkage at the EKV1/EKV2 locus, but no mutation has been identified. We describe in the present Exome Sequencing and Validation of Variants study the mapping of the gene for this unique syndrome on Three affected individuals (V-3, V-5, and V-24) from distinct chromosome 6p12.3-q16.1, as well as the identification of a branches of the family (Figure 1A) were selected for exome se- p.L168F (c.504G>C) mutation in the gene ELOVL4 (RefSeq NM quencing. Genomic DNA (5 μg) was fragmented and enriched _022726) by using whole-exome sequencing. The p.L168F mu- (SureSelect Human All Exon V4 kit; Agilent Technologies). tation segregates well with the disease, and we provide de- The prepared library was sequenced with paired-end reads tailed clinical characterization of 19 mutation-positive (HiSeq 2000; Illumina). The reads were mapped against the individuals from this family. human genome (hg19) (Burrows-Wheeler Aligner; http: //bio-bwa.sourceforge.net). Reads with a unique mapping lo- cation were kept for downstream analysis. Gene Analysis Tool Methods Kit (Broad Institute; http://www.broadinstitute.org/gatk/) and ANNOVAR (http://www.openbioinformatics.org/annovar/) Participants were used for the calling of single-nucleotide variations, small We investigated an FC kindred presenting a combination of insertions, and small deletions (indels). Called variants were erythrokeratodermia with ataxia. The description of clinical filtered against dbSNP132 as well as individuals from our in- phenotypes of the early generations of the family has been house exome database. For the validation of next-generation previously described.3 We collected genomic DNA from 32 sequencing variants, primers were designed with the soft- individuals of this family. These individuals underwent ware Primer 3 (http://bioinfo.ut.ee/primer3-0.4.0/) to am- complete neurologic and dermatologic examinations. Mea- plify the coding region encompassing the putative variation. surement of long-chain fatty acids (C22, C24, and C26) was performed on 2 affected individuals (V-3 and V-24 Sequencing of ELOVL4 in Patients With SCA [Figure 1A]) (Centre Hospitalier Universitaire de Sherbrooke). We sequenced all of the coding exons as well as 20 bp of the An additional cohort of 95 patients with unexplained SCA exon-intron boundaries of the gene ELOVL4 in 95 patients was used for gene screening. After participants provided with SCA. Polymerase chain reaction primers were designed written informed consent, genomic DNA was extracted from using Primer 3. The primer sequences and polymerase chain

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Figure 1. Identification and Characterization of a Missense Mutation in ELOVL4

A 12 34 Ataxia + EKV Male I EKV Female Ataxia Sex unknown Possibly affected Deceased Unaffected 12 3456 II

1 2 3 4 5 6 7 8 9 10 11 III

12 3 456789101112 13 14 15 16 17 18 IV –+++–+––+

12 3 4 5 6 7 8 9 10141516171819202122232425 V 4 –– + +– + – + + + + + +

12 345 6 7 91011 VI 2 ++ –+ + ––+

B * c.504G>C C

Mutant TM1 TM2 TM3 TM4 TM5 A T G T T T A C C T T C T G G T G G A T T

TM3

Wild type Mutant A T G T T T A C C T T G T G G T G G A T T FLHVYHHCTMFTF WWIGI Homo sapiens FLHVYHHCTMFTLWWIGI * p.L168F Macaca mulatta FLHVYHHCTMFTLWWIGI Mus musculus FLHVYHHCTMFTLWWIGI MFTF WW I Canis lupus FLHVYHHCTMFTLWWIGI Mutant Musca domestica FLHVYHHCTMFTLWWIGI A T G T T T A C C T T C T G G T G G A T T Gallus gallus FLHVYHHCTMFTLWWIGI Danio rerio FLHVYHHCTMFTLWWIGI MF T LWW I Wild type A T G T T T A C C T T G T G G T G G A T T

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

reaction conditions are available on request. The amplicons sis revealed 3 positive chromosomal regions with a logarithm were then sequenced (ABI 3730xl DNA Analyzer; Life Tech- of odds score superior to 1.5 on chromosomes 1, 6, and 7 (data nologies) and analyzed (Mutation Surveyor, version 3.0; not shown). Further analysis with additional markers and ad- Softgenetics). ditional 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 al- Results lowed the identification of a candidate locus of 46.8 mega- bases between markers D6S459 and D6S417 at chromosome Linkage Analysis and Exome Sequencing 6p12.3-q16.1 (Supplement [eFigure]). We also performed com- We first excluded linkage at the EKV1/EKV2 and MEDNIK loci parative genomic hybridization analysis that did not reveal sig- in the FC family (data not shown). Genome-wide linkage analy- nificant copy number variations in this candidate gene re-

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Figure 2. Clinical Phenotype of the French-Canadian Family

A B

C D

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.

gion. In turn, whole-exome sequencing allowed us to identify (Figure 2B). Both types of lesions are usually symmetrically dis- a p.L168F (c.504G>C) mutation in ELOVL4 (Figure 1B) (Ref- tributed and vary in severity among patients, becoming worse Seq NM_022726), a gene located in the candidate interval in winter and improving with the use of emollients. The on- (Supplement [eTable 1]). This genetic variation was found in set is in early infancy and, in most cases, the lesions disap- the 3 affected individuals (V-3, V-5, and V-24). Sanger sequenc- pear after the patient is 25 years of age. In all patients, hair, nails, ing confirmed that this genetic variation segregated with the and scalp were normal. No hearing impairment was de- disease haplotype in 19 individuals. This mutation was not tected, and cognition appeared normal. The onset of gait ataxia found in 189 additional control individuals, nor was it found usually occurred in the fourth or fifth decade of life (mean, 51 in public databases, such as 1000 Genomes (http://browser years), but it could occur as early as the third decade in some .1000genomes.org) and Exome Variant Server (http://evs.gs patients. The progression of gait disturbance is very slow. Pa- .washington.edu/EVS). Screening of 95 additional patients with tients may need to use a cane after 10 years of disease progres- SCA failed to identify additional mutations in ELOVL4. sion. The affected individuals in the present study usually re- quired a walker in their mid-60s or 70s, although other medical Clinical Manifestations of Mutation Carriers conditions may have contributed to the gait disturbance (eg, The summary of the detailed clinical examination performed aortic aneurysm, metastatic breast cancer, chronic alcohol con- on 19 mutation carriers from the FC family is reported in the sumption, and severe emphysema) (Supplement [eTable 2]). Supplement (eTable 2). Erythrokeratodermia variabilis (n = 3), Magnetic resonance imaging conducted in 7 individuals with ataxia (n = 1), or a combination of both phenotypes (n = 11) was mild or moderate ataxia showed cerebellar and pontine atro- found in the mutation carriers; the others were unaffected. As phy (Figure 2C). In these affected individuals, the atrophy was previously described,3 2 types of skin lesions can be distin- more severe in the vermis than in the cerebellar hemi- guished. First, erythematous and hyperkeratotic plaques are spheres. In turn, 2 individuals with EKV lesions without ataxia most commonly observed over the dorsal aspects of the hands had normal magnetic resonance imaging findings. Individual and feet, the elbows, the ankles, and the external ears. The hy- V-24, who had EKV lesions and very mild ataxia, also exhib- perkeratosis usually is more prominent than the erythema, and ited cerebellar hypometabolism on 18F-fluorodeoxyglucose– a fine scaling is observed over those persistent plaques positron emission tomography (Figure 2D). An electromyo- (Figure 2A). Second, transient, figurate, and erythematous gram obtained in 8 affected family members, including 1 study patches are observed over the legs, thighs, and buttocks participant (13%) with EKV lesions only, disclosed mild axo-

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nal peripheral neuropathy in 4 of the 8 individuals (50%) exert a dominant negative effect on the wild-type protein to (Supplement [eTable 2]). The mutation was also found in 4 in- form aggresomes of both normal and aberrant Elovl4. Inter- dividuals (V-16, VI-4, VI-6, and VI-11; 21%) (Figure 1A) with- estingly, 2 additional homozygous mutations were found in pa- out any neurologic manifestations or skin lesions. Lipid analy- tients with ichthyosis and severe neurologic disturbances, such sis from whole-blood samples of 2 affected individuals (V-3 and as spastic paraplegia and neurodevelopmental defects.14 The V-24) did not reveal abnormal levels of long-chain fatty acids p.L168F missense mutation described in the present study is (C22, C24, and C26). However, the linoleic acid level was slightly located within the third transmembrane domain (Figure 1C) above the reference range. 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 muta- Discussion tion will be necessary to understand the role of the mutation in the disease. It is possible that the localization of the muta- We evaluated a p.L168F mutation in ELOVL4 segregating with tion in the FC family in a different domain of the protein could SCA and EKV in a large FC family by using a combination of be responsible for the phenotypic differences observed in pa- genome scan and whole-exome sequencing. Based on the tients with Stargardt disease type 3. strong linkage found on chromosome 6p12.3-q16.1, we fil- In the present study, a total of 19 ELOVL4 p.L168F muta- tered for genetic variants and found the ELOVL4 mutation as tion carriers were identified for whom we obtained detailed the only coding genetic variation in 3 affected individuals who neurologic and physical examination results (Supplement were tested. The mutation segregates well with the disease phe- [eTable 2]). Most (11 [58%]) individuals bearing the p.L168F notype and was not found in control individuals or in public mutation exhibited a combination of EKV and ataxia. Other databases. Moreover, ELOVL4 is a very good candidate gene mutation carriers (3 [16%]) showed only EKV, most likely because mutations, in both human and animal models, have because they were younger (aged 36, 33, and 44 years). One been associated14,15 with skin defects and neurologic impair- (5%) mutation carrier showed cerebellar ataxia at 55 years, ments. Taken together, our data are consistent with the iden- without apparent skin lesions. The EKV lesions are usually tification of ELOVL4 as the causative gene for the EKV and SCA apparent during childhood, may be minimized by hydrating in this FC family. lotions, and in some instances disappear over time. There- The ELOVL4 gene encodes for a member of the elongase fore, we cannot exclude that EKV has been overlooked in family and is involved in the elongation of very long-chain this individual despite careful assessment. Alternatively, fatty acids. The Elovl4 protein is expressed in the retina, incomplete penetrance for the skin phenotype may exist. brain, testes, and skin.16 As a 314–amino acid protein, Elovl4 Finally, we have identified asymptomatic mutation carriers is predicted to have 5 transmembrane segments, a histamine (4 [21%]), suggesting incomplete penetrance for EKV cluster dideoxy binding motif, and a dilysine endoplasmic (Supplement [eTable 2]). Because of their relatively young reticulum retention motif (Figure 1C).17 Biochemical age and considering the late-onset disease course of the analysis18 revealed its implication in the biosynthesis of very ataxic features, it is possible that these carriers may eventu- long-chain fatty acids, specifically elongating both saturated ally become symptomatic. and unsaturated C26 to C28 products and C28 to products of The heterogeneity of clinical manifestations associated 30 to 38 carbons. Very long-chain fatty acids participate in a with mutations in ELOVL4 in humans is intriguing. Although wide variety of physiological functions, including skin bar- originally described in macular degeneration (Stargard dis- rier formation14 and peroxisome β-oxidation, which is ease type 3) without skin lesions, homozygous mutations have known to be involved in several neurodevelopmental been associated14 with ichthyosis, encephalopathy, and epi- disorders.19 After differentiation of the keratinocytes, differ- lepsy, without macular degeneration. In our FC family, EKV ent layers of the epidermis are developed, including the stra- lesions were reminiscent of ichthyosis, but we found no clini- tum corneum.20 This outermost layer of the epidermis acts cal evidence of macular degeneration. In Elovl4 knockout mice, as a transepidermal barrier that prevents dehydration. It is skin lesions appear to be a common feature, but depletion of mainly composed of ceramides containing ω-hydroxy long- very long-chain polyunsaturated fatty acids in the retina does chain fatty acids. Interestingly, knockout mice for Elovl4 die not seem to affect visual function.28 These observations are several hours after birth and show severe skin atrophy. They consistent with other EKV and ichthyosis genes that are asso- also display reduced body movement, suggesting abnormal ciated with heterogeneous neurologic manifestations.4,6 neurologic behavior.21 The gene ELOVL4 has been associated22-24 with a juve- nile form of macular degeneration: Stargardt disease type 3 Conclusions (STGD3; OMIM 600110). The disease segregates in an autosomal dominant pattern of inheritance, and patients heterozy- To our knowledge, we have described, for the first time, a mis- gous for these mutations show progressive macular degen- sense mutation in the gene ELOVL4 associated with SCA as well eration and loss of central vision. Three pathogenic variants as EKV. Finding additional mutations in ELOVL4 in other SCA have been reported,25 resulting in a truncated protein lacking families, as well as functional characterization of these muta- the dilysine endoplasmic reticulum retention motif. In vitro tions, should provide additional insights on disease patho- studies17 have shown that mutant proteins are mislocalized and genesis.

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ARTICLE INFORMATION 4. Scott CA, Tattersall D, O’Toole EA, Kelsell DP. 17. Grayson C, Molday RS. Dominant negative Accepted for Publication: December 26, 2013. Connexins in epidermal homeostasis and skin mechanism underlies autosomal dominant disease. Biochim Biophys Acta. 2012;1818(8): Stargardt-like macular dystrophy linked to Published Online: February 24, 2014. 1952-1961. mutations in ELOVL4. J Biol Chem. doi:10.1001/jamaneurol.2013.6337. 5. López-Bigas N, Olivé M, Rabionet R, et al. 2005;280(37):32521-32530. Author Contributions: Dr Cossette had full access Connexin 31 (GJB3) is expressed in the peripheral 18. Agbaga MP, Brush RS, Mandal MN, Henry K, to all the data in the study and takes responsibility and auditory nerves and causes neuropathy and Elliott MH, Anderson RE. Role of Stargardt-3 for the integrity of the data and the accuracy of the hearing impairment. Hum Mol Genet. macular dystrophy protein (ELOVL4) in the data analysis. 2001;10(9):947-952. biosynthesis of very long chain fatty acids. Proc Natl Study concept and design: Cadieux-Dion, Acad SciUSA. 2008;105(35):12843-12848. Turcotte-Gauthier, Rouleau, Cossette. 6. Montpetit A, Côté S, Brustein E, et al. Disruption Acquisition of data: Cadieux-Dion, of AP1S1, causing a novel neurocutaneous 19. Verheijden S, Bottelbergs A, Krysko O, et al. Turcotte-Gauthier, Noreau, Martin, Meloche, syndrome, perturbs development of the skin and Peroxisomal multifunctional protein-2 deficiency Gravel, Drouin, Nguyen. spinal cord. PLoS Genet. 2008;4(12):e1000296. causes neuroinflammation and degeneration of Analysis and interpretation of data: Cadieux-Dion, doi:10.1371/journal.pgen.1000296. Purkinje cells independent of very long chain fatty Turcotte-Gauthier, Martin, Drouin, Nguyen. 7. Caramins M, Colebatch JG, Bainbridge MN, et al. acid accumulation. Neurobiol Dis. 2013;58:258-269. Drafting of the manuscript: Cadieux-Dion, Exome sequencing identification of a GJB1 missense 20. Rissmann R, Groenink HW, Weerheim AM, Turcotte-Gauthier, Nguyen, Cossette. mutation in a kindred with X-linked spinocerebellar Hoath SB, Ponec M, Bouwstra JA. New insights into Critical revision of the manuscript for important ataxia (SCA-X1). Hum Mol Genet. 2013;22(21): ultrastructure, lipid composition and organization intellectual content: Noreau, Martin, Meloche, 4329-4338. of vernix caseosa. J Invest Dermatol. Gravel, Drouin, Rouleau. 8. Richard G, Lin JP, Smith L, et al. Linkage studies 2006;126(8):1823-1833. Obtained funding: Rouleau, Cossette. in erythrokeratodermias: fine mapping, genetic 21. Li W, Sandhoff R, Kono M, et al. Depletion of Administrative, technical, or material support: heterogeneity and analysis of candidate genes. ceramides with very long chain fatty acids causes Meloche, Gravel. J Invest Dermatol. 1997;109(5):666-671. defective skin permeability barrier function, and Study supervision: Nguyen, Cossette. 9. Seidel K, Siswanto S, Brunt ER, den Dunnen W, neonatal lethality in ELOVL4 deficient mice. Int J Conflict of Interest Disclosures: None reported. Korf HW, Rüb U. Brain pathology of spinocerebellar Biol Sci. 2007;3(2):120-128. Funding/Support: Mr Cadieux-Dion is supported ataxias. Acta Neuropathol. 2012;124(1):1-21. 22. Maugeri A, Meire F, Hoyng CB, et al. A novel by the Réseau de Médecine Génétique Appliquée 10. Kinirons P, Verlaan DJ, Dubé MP, et al. A novel mutation in the ELOVL4 gene causes autosomal and La Fondation GO. Ms Martin and Dr Nguyen are locus for idiopathic generalized epilepsy in dominant Stargardt-like macular dystrophy. Invest supported by the Fonds de Recherche du French-Canadian families maps to 10p11. Am J Med Ophthalmol Vis Sci. 2004;45(12):4263-4267. Québec–Santé. Drs Rouleau and Cossette are Genet A. 2008;146A(5):578-584. 23. Bernstein PS, Tammur J, Singh N, et al. Diverse supported by the Canadian Institutes of Health macular dystrophy phenotype caused by a novel Research. Ms Noreau received the Doctoral 11. Saillour Y, Cossée M, Leturcq F, et al. Detection of exonic copy-number changes using a highly complex mutation in the ELOVL4 gene. Invest Award–Frederick Banting and Charles Best Ophthalmol Vis Sci. 2001;42(13):3331-3336. Graduate Scholarship from the Canadian Institutes efficient oligonucleotide-based comparative of Health Research. genomic hybridization-array method. Hum Mutat. 24. Zhang K, Kniazeva M, Han M, et al. A 5-bp 2008;29(9):1083-1090. deletion in ELOVL4 is associated with two related Role of the Sponsor: The sponsors had no role in 12. van de Leemput J, Chandran J, Knight MA, et al. forms of autosomal dominant macular dystrophy. the design and conduct of the study; collection, Nat Genet. 2001;7(1)89-93. management, analysis, and interpretation of the Deletion at ITPR1 underlies ataxia in mice and data; preparation, review, or approval of the spinocerebellar ataxia 15 in humans. PLoS Genet. 25. Harkewicz R, Du H, Tong Z, et al. Essential role manuscript; and decision to submit the manuscript 2007;3(6):e108. doi:10.1371 of ELOVL4 protein in very long chain fatty acid for publication. /journal.pgen.0030108. synthesis and retinal function. J Biol Chem. 2012;287(14):11469-11480. Additional Contributions: We thank the FC family 13. Sharp AJ, Mefford HC, Li K, et al. A recurrent for their participation in the study. Yves Léo 15q13.3 microdeletion syndrome associated with 26. Choi Y, Sims GE, Murphy S, Miller JR, Chan AP. Lamarre, MD, Department of Neurology, Notre mental retardation and seizures. Nat Genet. Predicting the functional effect of amino acid Dame Hospital, Montreal, reviewed all nerve 2008;40(3):322-328. substitutions and indels. PLoS One. conduction studies and electromyographic 14. Aldahmesh MA, Mohamed JY, Alkuraya HS, 2012;7(10):e46688. doi:10.1371 recordings. et al. Recessive mutations in ELOVL4 cause /journal.pone.0046688. ichthyosis, intellectual disability, and spastic 27. Adzhubei IA, Schmidt S, Peshkin L, et al. A REFERENCES quadriplegia. Am J Hum Genet. 2011;89(6): method and server for predicting damaging 1. Cagnoli C, Mariotti C, Taroni F, et al. SCA28, a 745-750. missense mutations. Nat Methods. novel form of autosomal dominant cerebellar ataxia 15. McMahon A, Butovich IA, Kedzierski W. 2010;7(4):248-249. on chromosome 18p11.22-q11.2. Brain. 2006;129(pt Epidermal expression of an Elovl4 transgene 28. Barabas P, Liu A, Xing W, et al. Role of ELOVL4 1):235-242. rescues neonatal lethality of homozygous Stargardt and very long-chain polyunsaturated fatty acids in 2. Lee YC, Durr A, Majczenko K, et al. Mutations in disease-3 mice. J Lipid Res. 2011;52(6):1128-1138. mouse models of Stargardt type 3 retinal KCND3 cause spinocerebellar ataxia type 22. Ann 16. Molday RS, Zhang K. Defective lipid transport degeneration. Proc Natl Acad SciUSA. Neurol. 2012;72(6):859-869. and biosynthesis in recessive and dominant 2013;110(13):5181-5186. 3. Giroux JM, Barbeau A. Erythrokeratodermia with Stargardt macular degeneration. Prog Lipid Res. ataxia. Arch Dermatol. 1972;106(2):183-188. 2010;49(4):476-492.

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