region (p ¼ 4.36 3 10
); absence of a genomic mechanism
that might cause the disease, such as repeat expansions,
deletions, and/or duplications; and extensive coding-
sequence analysis of the region. Additionally, on the basis
of its role in the NGF pathway and animal studies, IFRD1 is
a strong a priori biological candidate for SMNA. Mutation in
genes that are part of NGF pathway, NTRK1 and NGFB,
cause HSAN IV and HSAN V. Existing knockout-animal
models have neurological phenotypes such as muscle
atrophy and axonal-growth dysregulation, consistent
with its possible role in a neurodegenerative disorder like
SMNA. Our bioinformatic analysis of mutant IFRD1 indi-
cates that the observed mutation might affect binding
and transport through the nuclear pore complexes. Altered
membrane trafﬁcking of signaling molecules has been
proposed as a mechanism that when dysregulated can
lead to neuropathies because of extreme polarity and size
of peripheral neurons. The weakness of the study is that
we have not unequivocally demonstrated that mutation
in IFRD1 causes SMNA. It remains possible that IFRD1
I172V is a rare variant and that some other change in the
original interval undetected by our approach is causative.
Also, we have not excluded changes in PTPRZ1 and
C7orf60 as causative. However, PTPRZ1 is unlikely to be
causal, given that the gene and the identiﬁed variant are
poorly conserved. The C7orf60 gene and the variant identi-
ﬁed are not as well conserved as IFRD1. Functional studies of
the IFRD1 I172V mutant gene could provide support for its
pathogenicity and provide additional insights into mecha-
nisms by which the mutant protein causes disease.
However, ultimately, proof that mutations in IFRD1 cause
SMNA will be provided by identiﬁcation of other familial
and sporadic cases with similar phenotypes. For 83 patients
with ataxia available in our laboratory we have screened all
the exons of IFRD1 and have not identiﬁed any additional
mutations. However, neuropathy is not a component of
ataxias in our sample. Further screening of IFRD1 for muta-
tion in patients with related phenotypes that include
neuropathy is warranted.
We are grateful to the members of the family for their participation
in these studies and to Elizabeth Thompson for her intellectual
contributions during the early stages of the research. Skillful tech-
nical assistance was provided by Ruolan Qiu, Choli Lee, Emily
Turner, Sarah Summer, Zarshid Arbibi, Ruben Burbank, Catherine
Morgan, Jane Ranchalis, and John Wolf. We thank Chang-En Yu
for generous provision of control samples. The research was sup-
ported in part by funds and resources from the National Organiza-
tion for Rare Disorders, the Department of Veterans Affairs, the
Mary Gates and the Herschel and Caryl Roman Endowments for
Students, and NIH/NHGRI grant R21HG004749 to J.S.
Received: February 6, 2009
Revised: April 4, 2009
Accepted: April 13, 2009
Published online: April 30, 2009
The URLs for data presented herein are as follows:
GeneReviews at GeneTests, http://www.genetests.org
Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.
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