We have addressed each of the reviewers comments point by point below, and marked all changes to the revised manuscript in red.

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1 Author s response to reviews Title: A novel frameshift GRN mutation results in frontotemporal lobar degeneration with a distinct clinical phenotype in two siblings: case report and literature review Authors: Takashi Hosaka (dagasi1985@yahoo.co.jp) Kazuhiro Ishii (kazishii@md.tsukuba.ac.jp) Takeshi Miura (tmiur@bri.niigata-u.ac.jp) Naomi Mezaki (nm8@bri.niigata-u.ac.jp) Kensaku Kasuga (ken39@bri.niigata-u.ac.jp) Takeshi Ikeuchi (ikeuchi@bri.niigata-u.ac.jp) Akira Tamaoka (atamaoka@md.tsukuba.ac.jp) Version: 1 Date: 18 Jul 2017 Author s response to reviews: 14 July 2017 Dear Editors, Re: NURL-D We kindly request that you consider our revised manuscript, entitled A novel frameshift GRN mutation results in frontotemporal lobar degeneration with a distinct clinical phenotype in two siblings: case report and literature review for publication in BMC Neurology. We greatly appreciate the reviewers attention to our paper, and believe that their comments and suggestions were very constructive and strengthened the quality of our manuscript considerably. We have addressed each of the reviewers comments point by point below, and marked all changes to the revised manuscript in red.

2 Point-by-point response to the reviewers comments Daniela Galimberti (Reviewer 1): According to NCBI, the mutation should be named "p.pro373argx38" (NCBI Reference Sequence: NC_ ). Please check Thank you for your comment. We corrected p.pro373argfsx37 to p.pro373argx38 accordingly (Abstract, line 17, page 2; Case presentation, line 9, page 8; and Figures legends, line 9, page 17). The family history should be included, i.e. is the brother alive? Is there any information on her parents? The patient s brother and parents had already passed away at the time of writing this case. Therefore, we could not obtain their detailed clinical information. We added this explanation in the text (Case presentation, lines 16 17, page 5). Introduction: additional examples of phenotypic heterogeneity should be included (JAD 2011;24;253-9 and 2011;23:7-12) As you suggested, we added There are also reports of clinical heterogeneity within a family. in the Background section (lines 16 17, page 4). We also added the following references to the text and Table 1: Pietroboni AM, Fumagalli GG, Ghezzi L, Fenoglio C, Cortini F, Serpente M, et al. Phenotypic heterogeneity of the GRN Asp22fs mutation in a large Italian kindred. J. Alzheimers Dis. 2011;24: Rossi G, Piccoli E, Benussi L, Caso F, Redaelli V, Magnani G, et al. A novel progranulin mutation causing frontotemporal lobar degeneration with heterogeneous phenotypic expression. J. Alzheimers Dis. 2011;23:7 12. Discussion: beside clinical heterogeneity associated with the same mutation, it should be acknowledged that sometimes the same mutations results in the same phenotype in monozygotic twin pairs (Neurology 2012; 78(16):1245-9).

3 As you suggested, we added Similar symptoms, neuropsychological profile, and neuroimaging findings have been reported in a monozygotic twin pair with a GRN mutation. in the Discussion section (lines 9 10, page 9). We also added the following reference to the text: McDade E, Boeve BF, Burrus TM, Boot BP, Kantarci K, Fields J, et al. Similar clinical and neuroimaging features in monozygotic twin pair with mutation in progranulin. Neurology 2012;78: David Weidman (Reviewer 2): 1) Regarding the Western Aphasia Battery from the description in the paper, it is not clear that an auditory verbal comprehension subtest was administered (doesn't seem like it was done). While different subtests can be chosen for the WAB, if "visual input" tasks were done, by which I assume that means reading comprehension, I think that merits that a complementary auditory comprehension test(s) be done. There is a later reference to retained ability to understand words, but objective means of establishing that should include auditory comprehension Thank you for your suggestion. We revised the text as follows: Language function was assessed using the Western Aphasia Battery (WAB) Japanese edition once and SLTA (standard language test of aphasia) two times within two months. The scores of WAB subtests were as follows: spontaneous speech, 13 points; auditory verbal comprehension, 5.5 points; repetition, 0 points; naming, 0 points; reading, 4.3 points; writing, 2.2 points; praxis, 6.8 points; and construction, drawing, block design & calculation, 6.6 points. Raven s score was 25/37 (average ± standard deviation: 26.9 ± 5.4). Aphasia quotient was The results of SLTA were similar to those of WAB. Naming, writing, and repetition were impaired. However, auditory verbal comprehension and reading concerning words and short sentences were relatively preserved. Spatial perception and visual perception were also normal. Verbal comprehension via visual perception was approximately normal. Therefore, it is likely that auditory verbal comprehension was complemented by visual perception. (Case presentation, lines 7 17, page 6). 2) Regarding the patient's elder brother being diagnosed as having CBS, it's not clear if that's purely clinically. Does this imply that there was no genetic analysis of the brother? Is he deceased, so no blood available, and if he was deceased at the time of the genetic analysis of the patient, had a brain autopsy been carried out?

4 If these details of the elder brother can't be ascertained, would state this limitation in the discussion paragraph The patient s brother had already passed away and a brain autopsy was not carried out. Therefore, we could not perform a genetic analysis. Moreover, he was diagnosed as CBS in another hospital and we could not obtain his detailed clinical information. We added some of this information in the Discussion paragraph (Discussion and conclusions, lines 11 13, page 9). 3) Regarding the first discussion paragraph, the phrase: "whereas behavioral disinhibition and memory impairments were not observed in the early stages of disease", I'd suggest adding "and executive function", to the retained function early on, if that was the case in this patient, since bvftd may present as disinhibition (orbital frontal) or executive dysfunction, reduced planning (dorsolateral frontal). Perhaps can read: "whereas behavioral disinhibition, executive dysfunction and memory impairment were not impaired " Thank you for your comment. We corrected whereas behavioral disinhibition and memory impairments were not observed in the early stages of disease to whereas behavioral disinhibition, executive function, and memory impairments were not impaired in the early stages of disease (Discussion and conclusions, lines 4 5, page 9). 4) Contrasting haploinsufficiency in autosomal dominant genetic conditions, compared to recessive, perhaps a brief comment, or perhaps contrasting with a toxic gain of function or toxicity of excessive proteins in many autosomal dominant conditions (eg, familial AD, early onset, PSN-1) Haploinsufficiency is a cause of autosomal genetic conditions when the protein expressed by a single allele is not sufficient to maintain its normal function. It differs from recessive disease. As you commented, in many autosomal dominant conditions, toxic gain of function or toxicity of excessive proteins are the cause of disease. However, haploinsufficiency causes disease by loss of function. Actually, in cases of mutated GRN, loss-of-function mutations have been reported as the cause of FTLD. As described in the text, in a heterozygous GRN mutation carrier, there is an approximate 50% decrease in mrna and 33% decrease in progranulin protein levels. In our case, a mutant allele product was not detected, suggesting degradation of the mutant allele by the nonsense-mediated RNA decay system; haploinsufficiency due to reduced expression of progranulin was considered to be a possible pathogenic mechanism (Case presentation, lines 12 14, page 8; Discussion and conclusions, lines 8 11, page 10).

5 We added the following references: Cook DL, Gerber AN, Tapscott SJ. Modeling stochastic gene expression: implications for haploinsufficiency. Proc. Natl. Acad. Sci. U. S. A. 1998;95: Davis JA, Naruse S, Chen H, Eckman C, Younkin S, Price DL. An Alzheimer's disease-linked PS1 variant rescues the developmental abnormalities of PS1-deficient embryos. Neuron 1998;20: Qian S, Jiang P, Guan XM, Singh G, Trumbauer ME, Yu H. Mutant human presenilin 1 protects presenilin 1 null mouse against embryonic lethality and elevates Abeta1-42/43 expression. Neuron. 1998;20: We correct understood to understand (Case presentation, line 10, page 7) and revised the reference numbers because some references were added. We greatly appreciate your consideration concerning the publication of our manuscript. Sincerely, Dr. Kazuhiro Ishii Department of the Neurology, Division of Clinical Medicine Faculty of Medicine, University of Tsukuba Ten'noudai, Tsukuba, Ibaraki, , Japan Tel: , Fax: kazishii@md.tsukuba.ac.jp

Takashi Hosaka 1, Kazuhiro Ishii 1*, Takeshi Miura 2,3, Naomi Mezaki 2,3, Kensaku Kasuga 2, Takeshi Ikeuchi 2 and Akira Tamaoka 1

Takashi Hosaka 1, Kazuhiro Ishii 1*, Takeshi Miura 2,3, Naomi Mezaki 2,3, Kensaku Kasuga 2, Takeshi Ikeuchi 2 and Akira Tamaoka 1 Hosaka et al. BMC Neurology (2017) 17:182 DOI 10.1186/s12883-017-0959-2 CASE REPORT Open Access A novel frameshift GRN mutation results in frontotemporal lobar degeneration with a distinct clinical phenotype

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