Analysis of IFT74as a candidate gene for chromosome 9p-linked ALS-FTD
- Parastoo Momeni†1,
- Jennifer Schymick†1,
- Shushant Jain†1,
- Mark R Cookson1,
- Nigel J Cairns2, 3,
- Elisa Greggio1,
- Matthew J Greenway4,
- Stephen Berger1,
- Stuart Pickering-Brown5,
- Adriano Chiò6,
- Hon Chung Fung1,
- David M Holtzman2,
- Edward D Huey7,
- Eric M Wassermann7,
- Jennifer Adamson8,
- Michael L Hutton8,
- Ekaterina Rogaeva9,
- Peter St George-Hyslop9,
- Jeffrey D Rothstein10,
- Orla Hardiman11,
- Jordan Grafman7,
- Andrew Singleton1,
- John Hardy1Email author and
- Bryan J Traynor12
© Momeni et al; licensee BioMed Central Ltd. 2006
Received: 03 August 2006
Accepted: 13 December 2006
Published: 13 December 2006
A new locus for amyotrophic lateral sclerosis – frontotemporal dementia (ALS-FTD) has recently been ascribed to chromosome 9p.
We identified chromosome 9p segregating haplotypes within two families with ALS-FTD (F476 and F2) and undertook mutational screening of candidate genes within this locus.
Candidate gene sequencing at this locus revealed the presence of a disease segregating stop mutation (Q342X) in the intraflagellar transport 74 (IFT74) gene in family 476 (F476), but no mutation was detected within IFT74 in family 2 (F2). While neither family was sufficiently informative to definitively implicate or exclude IFT74 mutations as a cause of chromosome 9-linked ALS-FTD, the nature of the mutation observed within F476 (predicted to truncate the protein by 258 amino acids) led us to sequence the open reading frame of this gene in a large number of ALS and FTD cases (n = 420). An additional sequence variant (G58D) was found in a case of sporadic semantic dementia. I55L sequence variants were found in three other unrelated affected individuals, but this was also found in a single individual among 800 Human Diversity Gene Panel samples.
Confirmation of the pathogenicity of IFT74 sequence variants will require screening of other chromosome 9p-linked families.
Amyotrophic lateral sclerosis (ALS, Online Mendelian Inheritance in Man (OMIM) 105400) is characterized by progressive motor neuron degeneration resulting in paralysis and death, usually from respiratory failure, within 3 to 5 years of symptom onset. ALS is typically sporadic in nature. However, 5–10% of cases are familial, and the identification of causal mutations has provided insight into the disease processes that lead to neurodegeneration [2–5]. Frontotemporal dementia (FTD, OMIM 600274) is a degenerative disorder of the frontal and anterior temporal lobes  and is the second most common cause of dementia accounting for approximately 20% of pre-senile cases . The syndrome is characterized clinically by initial behavioral and psychological disturbances, followed by cognitive decline eventually leading to dementia and death within a median of seven years from symptom onset . There is a family history of dementia in over 40% of FTD cases suggesting genetic components .
Clinical and pathological data indicate that ALS and FTD can form a spectrum of disease . Approximately 5% of ALS patients have clinically florid dementia (ALS-FTD)  and roughly half of patients with "classical" ALS have subtle frontal and temporal lobe impairment . Many sporadic and familial FTD cases similarly develop clinical symptoms of motor neuron involvement during the course of their illness [12, 8]. Furthermore, ubiquitin inclusions and dystrophic neurites are the hallmark neuropathological findings common to ALS without cognitive impairment, ALS with cognitive impairment, ALS-FTD and "pure" FTD with a greater distribution and load of lesions being associated with cognitive impairment .
Subjects and samples
F2 was a three-generation, 16-member North American kindred, in which seven individuals had been diagnosed with ALS-FTD (figure 2b).
Patients with ALS fulfilled the El Escorial criteria for probable or definite ALS and were diagnosed by a consultant neurologist after exclusion of ALS mimic syndromes . Frontotemporal dementia was diagnosed by clinical and neuropsychological criteria. The diagnosis was confirmed by autopsy in one familial ALS-FTD case.
DNA was extracted by standard procedures after ethically approved, written informed consent was obtained. Ethical approval for collection of DNA and clinical phenotype information was provided by the National Institute of Aging Institutional Review Board, Baltimore, MD (protocol #2003-081). Polymerase chain reaction (PCR) was performed to amplify DNA with markers spaced across the known chromosome 9p21 locus. Markers were selected from the Applied Biosystems Prism Linkage Mapping Set Version 2.5 (ABI, Foster City, CA). Additional makers were chosen based on mapping information publicly available from the UNISTS database at the National Center for Biotechnology Information (NCBI). For allele identification, the PCR products were separated and scored using automated ABI 3100 sequencing equipment.
Sequencing of candidate genes
Genes in the extended Chromosome 9p ALS-FTD locus* that were excluded as candidate genes by sequencing
Samples in which the IFT74 gene was sequenced
NINDS ALS-FTD and FTD samples 
Toronto ALS-FTD and FTD samples 
Irish ALS-FTD and ALS samples 
Johns Hopkins ALS samples
New York Brain Bank ALS, ALS-FTD and FTD samples
University of Miami/National Parkinson Foundation ALS samples
Miscellaneous ALS, ALS-FTD and FTD samples
North American control samples*
Human Genome Diversity panel 
Primers used to sequence the 19 exons of IFT74
Exon 1 Forward
Exon 1 Reverse
Exon 2 Forward
Exon 2 Reverse
Exon 3 Forward
Exon 3 Reverse
Exon 4 Forward
Exon 4 Reverse
Exon 5 Forward
Exon 5 Reverse
Exon 6 Forward
Exon 6 Reverse
Exon 7 Forward
Exon 7 Reverse
Exon 8 Forward
Exon 8 Reverse
Exon 9 Forward
Exon 9 Reverse
Exon 10 Forward
Exon 10 Reverse
Exon 11 Forward
Exon 11 Reverse
Exon 12 Forward
Exon 12 Reverse
Exon 13 Forward
Exon 13 Reverse
Exon 14 Forward
Exon 14 Reverse
Exon 15 Forward
Exon 15 Reverse
Exon 16 Forward
Exon 16 Reverse
Exon 17 Forward
Exon 17 Reverse
Exon 18 Forward
Exon 18 Reverse
Exon 19 Forward
Exon 19 Reverse
cDNA from a marathon Rapid Amplification of cDNA Ends (RACE)-ready adult human brain library (BD Biosciences, CA) was used as a template to amplify overlapping fragments of the predicted 2 kilobase (kb) transcript. Overlapping primers within each exon were designed using ExonPrimer, and PCR and sequencing were carried out as described above.
Human brain soluble extracts (40 ug per lane) were separated on 4–20% sodium dodecyl sulphate – polyacrylamide gel electrophoresis (SDS-PAGE) gels and blotted using a goat polyclonal antibody to the C-terminus of IFT74 (anti-CMG1, Everest Biotech Ltd, Oxfordshire, UK) at a final antibody concentration of 0.5 ug mL-1. For competition experiments, antibody was pre-incubated with a 10-fold excess (w/w) of immunizing peptide (KTIVDALHSTSGN).
Primary cortical neurons were prepared from E18 rat pups using papain dissociation and were plated on poly-L-lysine coated glass coverslips at 106 cells per dish. After 5 days in vitro, cells were fixed with 4% paraformaldehyde, permeabilized with 0.1% saponin and stained with the goat polyclonal antibody to IFT74 at a concentration of 2.5 mg mL-1. Secondary antibody was donkey anti-goat IgG conjugated to AlexaFluor 488 (1:200, Molecular Probes, Carlsbad, CA) and nuclei were identified with TO-PRO3 (Molecular probes). Coverslips were imaged with a Zeiss LSM510 META confocal microscope using consistent gain and offset settings for samples stained with antibody alone or with antibody plus immunizing peptide. Secondary antibody alone gave no signal.
Previous linkage analysis of F2 using dinucleotide marker data had revealed a single region with a lod score of ~1.5 on chromosome 9p that matched with the published chromosome 9p21.3-p13.3 ALS-FTD locus (figure 2b). Similarly, marker data showed a haplotype across chromosome 9p that segregated with disease status in F476 (figure 2a). Based on these data, F476 and F2 were selected for mutational screening of the 14 candidate genes within the previously defined 2.1 Mb region of the chromosome 9p ALS-FTD locus.
In order to assess the prevalence of IFT74 sequence variants, we sequenced the entire coding region of this gene in a large number of ALS, ALS-FTD and FTD samples (Table 2). The Q342X mutation was not found in any of these patients. However, we identified a G58D (nt173 G to A) sequence variant in a Caucasian woman who developed sporadic semantic dementia without motor involvement at the age of 58 (II-1, figures 4b and 5). This G58D sequence variant was not found in 900 chromosomes from North American controls or in 1,600 chromosomes from the HGDP. We also identified an I55L sequence variant (nt163 A to T) in three additional affected probands; first, the I55L sequence variant was found in the proband of F549 who had been diagnosed with FTD at the age of 62 (figures 4c and 5). His 80-year-old brother (II-7) had been diagnosed with FTD at the age of 75 and carried the I55L sequence variant. A 70-year-old apparently unaffected sister (II-12) also carried the I55L sequence variant; second, the proband of F194, a 59-year-old Caucasian woman diagnosed with ALS-FTD, had the I55L sequence variant. Her sister had died of FTD and her paternal uncle had died of ALS-FTD (DNA samples not available); third, the I55L sequence variant was found in a 67-year-old man with sporadic ALS. He had presented one year before his death with bulbar symptoms including emotional lability, and had become increasingly withdrawn and indifferent to his symptoms during the course of his illness. I55L was not found in 900 chromosomes from North American controls, but it was found in 1 of 1,600 chromosomes from the HGDP in a French sample.
We found sequence variations in the IFT74 gene in patients with ALS-FTD, FTD and sporadic ALS. Five pieces of genetic information suggest that the IFT74 sequence variants are relevant to disease pathogenesis. First, the nonsense sequence variant (Q342X) segregates with disease in a small ALS-FTD kindred. Second, this premature stop codon significantly truncates the IFT74 protein in a manner likely to have a critical effect on the function of this plausible candidate gene. Third, additional sequence variants (G58D and I55L) were found in the IFT74 gene in other disease cases. Fourth, we have sequenced every known gene and predicted transcripts in the candidate region as defined by the minimal interfamily haplotype shared by the Dutch, Scandinavian and North American ALS-FTD families (figure 1) and the gene encoding IFT74 was the only gene that contained variants not identified in the general population and fifth, these mutations are not present in 900 to 1,000 North American control chromosomes.
Against these five pieces of suggestive information are four pieces of evidence against pathogenicity. First, we failed to find a mutation in the second family we used in our screening (F2). Second, the fact that the stop mutation is in the cDNA database in a sample of unknown provenance, third the fact that the I55L mutation is in a sample from France in the CEPH diversity series argues against the pathogenicity of that particular mutation. The genetic linkage reports indicate that mutations at the chromosome 9p locus are incompletely penetrant [14, 15] and this complicates the interpretation of both segregation data within families and of variants in control populations. Fourth: on contacting the senior authors of the original linkage report , they were unable to find a point variant in their linked family.
Our data indicate that IFT74 is a 600-residue, 69-kDa coiled-coil containing protein that localizes to the intracellular vesicle compartment. This protein is a component of the intraflagellar transport system responsible for vesicular transport of material synthesized within the cell body into and along the dendritic and axonal processes of human neurons. The importance of vesicle synthesis and axonal transport in motor neuron disease is increasingly recognized. Vesicle associated protein B missense (VAPB) mutations have been identified in familial ALS  and the wobbler mouse, an animal model of ALS, is caused by mutations in the vesicular protein sorting factor 54 . Dynactin is the motor protein responsible for retrograde axonal transport and mutations in the p150 subunit of this complex have been described in patients with ALS  and ALS-FTD . Furthermore, a mutation in the antegrade axonal transport kinesin gene, KIF1B, has been described in a single family with Charcot-Marie-Tooth disease-2A1, a hereditary motor and sensory axonal neuropathy (OMIM 118210). Given its role in vesicle transport, IFT74 is a plausible biological candidate to explain the neurodegeneration characteristic of both ALS and FTD phenotypes in a subset of patients. However, as the Q342X mutation was found in a cDNA library and in an (as yet) unaffected family member, there is currently no clear evidence that this mutation is of causal significance and IFT74 may just be a risk factor for ALS-FTD. Clearly, more work will be needed to determine its role, if any.
Intraflagellar transport 74 homolog (IFT74, also known as capillary morphogenesis protein 1 (CMG1); coiled-coil domain containing 2 (CCDC2); FLJ22621): GeneID 80173; UniGene Hs.145402; mRNA: AY040325 (gi:15418996); protein: AAK77221 (GI:15418997); SOD1 (NM_000454); MAPT (NM_016835); GRN (NM_002087).
Online Mendelian inheritance in man 
Amyotrophic lateral sclerosis [ALS, OMIM 105400]; Fronto-temporal dementia [FTD, OMIM 600274]; Fronto-temporal dementia/amyotrophic lateral sclerosis [ALS/FTD, OMIM 105550], Intraflagellar transport protein 74 (IFT74), previously CCDC2, CMG1 [OMIM 608040]
amyotrophic lateral sclerosis
frontotemporal dementia, IFT74, intraflagellar transport 74 homologue
online Mendelian inheritance in man
frontotemporal lobar degeneration
FTLD with ubiquitin-positive, tau-negative inclusions
motor neuron disease
national center for biotechnology information
superoxide dismutase one
microtubule-associated protein tau
Centre d'Etude du Polymorphisme Humain
Human Genome Diversity Panel
Rapid Amplification of cDNA Ends
sodium dodecyl sulfate-polyacrylamide gel electrophoresis
capillary morphogenesis protein 1
kinesin family member 1B.
We gratefully acknowledge the assistance of the New York Brain Bank – The Taub Institute, Columbia University (Federal grant number P50 AG08702) and the University of Miami/National Parkinson Foundation Brain Endowment Bank (funded by the National Parkinson Foundation, Inc., Miami, FL and other private donations). North American control samples for this study were obtained from the NINDS Neurogenetics repository at the Coriell Institute for Medical Research, Camden, NJ. This work was supported by NIH grant # P50 AG05681 (NJC). This research was supported (in part) by the Intramural Program of the NIA, NIMH and NINDS.
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