A novel ATRX mutation causes Smith‑Fineman‑Myers syndrome in a Chinese family

Li,Liangshan; Yu,Jing; Zhang,Xiao; Han,Mengmeng; Liu,Wenmiao; Li,Hui; Liu,Shiguo

doi:10.3892/mmr.2019.10818

A novel ATRX mutation causes Smith‑Fineman‑Myers syndrome in a Chinese family

Authors:
- Liangshan Li
- Jing Yu
- Xiao Zhang
- Mengmeng Han
- Wenmiao Liu
- Hui Li
- Shiguo Liu
View Affiliations

Affiliations: Medical Genetic Department, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China, Department of Clinical Laboratory, Medical College of Qingdao University, Qingdao, Shandong 266071, P.R. China, Health Physical Examination Center, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266000, P.R. China
Published online on: November 12, 2019 https://doi.org/10.3892/mmr.2019.10818
Pages: 387-392

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Smith‑Fineman‑Myers syndrome (SFMS) is a rare inherited disorder characterized mainly by mental retardation and anomalies in the appearance of patients. SFMS is caused by a mutation in the α‑thalassemia/mental retardation syndrome X‑linked (ATRX) gene and has an X‑linked recessive pattern. In the present study, a novel ATRX mutation was identified, and the association between its genotype and the phenotype was explored in a Chinese Han family with SFMS. This study aimed to lay a foundation for prenatal diagnosis for this family. Briefly, genomic DNA was extracted from peripheral blood samples obtained from the family. High‑throughput genetic sequencing was employed to detect the whole exome; subsequently, Sanger sequencing was performed to verify the candidate mutations. Clinical analysis of the proband was also accomplished. Consequently, a novel missense ATRX mutation was identified comprising a single nucleotide change of C to T, which caused an amino acid substitution at codon 172 in exon 7 (c.515C>T; p.Thr172Ile) of the proband. This mutation was found to co‑segregate in the present SFMS pedigree and was located in a highly conserved region of the ATRX protein, thus suggesting that it may be a pathogenic mutation. Taken together, these findings provided novel information that may lead towards an improved understanding of the genetic and clinical features of patients with SFMS, thereby facilitating a more accurate prenatal diagnosis of SFMS.

View Figures

View References

1	Al-Owain M, Kaya N, Al-Zaidan H, Al-Hashmi N, Al-Bakheet A, Al-Muhaizea M, Chedrawi A, Basran RK and Milunsky A: Novel intragenic deletion in OPHN1 in a family causing XLMR with cerebellar hypoplasia and distinctive facial appearance. Clin Genet. 79:363–370. 2011. View Article : Google Scholar : PubMed/NCBI
2	Borck G, Molla-Herman A, Boddaert N, Encha-Razavi F, Philippe A, Robel L, Desguerre I, Brunelle F, Benmerah A, Munnich A and Colleaux L: Clinical, cellular, and neuropathological consequences of AP1S2 mutations: Further delineation of a recognizable X-linked mental retardation syndrome. Hum Mutat. 29:966–974. 2008. View Article : Google Scholar : PubMed/NCBI
3	Ma QL, Yang F, Frautschy SA and Cole GM: PAK in Alzheimer disease, Huntington disease and X-linked mental retardation. Cell Logist. 2:117–125. 2012. View Article : Google Scholar : PubMed/NCBI
4	Lossi AM, Millan JM, Villard L, Orellana C, Cardoso C, Prieto F, Fontés M and Martínez F: Mutation of the XNP/ATR-X gene in a family with severe mental retardation, spastic paraplegia and skewed pattern of X inactivation: Demonstration that the mutation is involved in the inactivation bias. Am J Hum Genet. 65:558–562. 1999. View Article : Google Scholar : PubMed/NCBI
5	Badura-Stronka M, Jamsheer A, Materna-Kiryluk A, Sowińska A, Kiryluk K, Budny B and Latos-Bieleńska A: A novel nonsense mutation in CUL4B gene in three brothers with X-linked mental retardation syndrome. Clin Genet. 77:141–144. 2010. View Article : Google Scholar : PubMed/NCBI
6	des Portes V: X-linked mental deficiency. Handb Clin Neurol. 111:297–306. 2013. View Article : Google Scholar : PubMed/NCBI
7	Stevenson RE, Abidi F, Schwartz CE, Lubs HA and Holmes LB: Holmes-Gang syndrome is allelic with XLMR-hypotonic face syndrome. Am J Med Genet. 94:383–385. 2000. View Article : Google Scholar : PubMed/NCBI
8	Chudley AE, Lowry RB and Hoar DI: Mental retardation, distinct facial changes, short stature, obesity, and hypogonadism: A new X-linked mental retardation syndrome. Am J Med Genet. 31:741–751. 1988. View Article : Google Scholar : PubMed/NCBI
9	du Souich C, Chou A, Yin J, Oh T, Nelson TN, Hurlburt J, Arbour L, Friedlander R, McGillivray BC, Tyshchenko N, et al: Characterization of a new X-linked mental retardation syndrome with microcephaly, cortical malformation, and thin habitus. Am J Med Genet A 149A. 2469–2478. 2009. View Article : Google Scholar
10	Smith RD, Fineman RM and Myers GG: Short stature, psychomotor retardation, and unusual facial appearance in two brothers. Am J Med Genet. 7:5–9. 1980. View Article : Google Scholar : PubMed/NCBI
11	Stephenson LD and Johnson JP: Smith-Fineman-Myers syndrome: Report of a third case. Am J Med Genet. 22:301–304. 1985. View Article : Google Scholar : PubMed/NCBI
12	Wei J, Chen B, Jiang Y, Yang Y and Guo Y: Smith-Fineman-Myers syndrome: Report on a large family. Am J Med Genet. 47:307–311. 1993. View Article : Google Scholar : PubMed/NCBI
13	McPherson EW, Clemens MM, Gibbons RJ and Higgs DR: X-linked alpha-thalassemia/mental retardation (ATR-X) syndrome: a new kindred with severe genital anomalies and mild hematologic expression. Am J Med Genet. 55:302–306. 1995. View Article : Google Scholar : PubMed/NCBI
14	Gibbons RJ and Higgs DR: Molecular-clinical spectrum of the ATR-X syndrome. Am J Med Genet. 97:204–212. 2000. View Article : Google Scholar : PubMed/NCBI
15	Gibbons RJ, Picketts DJ, Villard L and Higgs DR: Mutations in a putative global transcriptional regulator cause X-linked mental retardation with alpha-thalassemia (ATR-X syndrome). Cell. 80:837–845. 1995. View Article : Google Scholar : PubMed/NCBI
16	Schenkel LC, Kernohan KD, McBride A, Reina D, Hodge A, Ainsworth PJ, Rodenhiser DI, Pare G, Bérubé NG, Skinner C, et al: Identification of epigenetic signature associated with alpha thalassemia/mental retardation X-linked syndrome. Epigenetics Chromatin. 10:102017. View Article : Google Scholar : PubMed/NCBI
17	Tang P, Park DJ, Marshall Graves JA and Harley VR: ATRX and sex differentiation. Trends Endocrinol Metab. 15:339–344. 2004. View Article : Google Scholar : PubMed/NCBI
18	Villard L and Fontes M: Alpha-thalassemia/mental retardation syndrome, X-Linked (ATR-X, MIM #301040, ATR-X/XNP/XH2 gene MIM #300032). Eur J Hum Genet. 10:223–225. 2002. View Article : Google Scholar : PubMed/NCBI
19	Chiurazzi P, Tabolacci E and Neri G: X-linked mental retardation (XLMR): From clinical conditions to cloned genes. Crit Rev Clin Lab Sci. 41:117–158. 2004. View Article : Google Scholar : PubMed/NCBI
20	Abidi FE, Cardoso C, Lossi AM, Lowry RB, Depetris D, Mattéi MG, Lubs HA, Stevenson RE, Fontes M, Chudley AE and Schwartz CE: Mutation in the 5′alternatively spliced region of the XNP/ATR-X gene causes Chudley-Lowry syndrome. Eur J Hum Genet. 13:176–183. 2005. View Article : Google Scholar : PubMed/NCBI
21	De La Fuente R, Viveiros MM, Wigglesworth K and Eppig JJ: ATRX, a member of the SNF2 family of helicase/ATPases, is required for chromosome alignment and meiotic spindle organization in metaphase II stage mouse oocytes. Dev Biol. 272:1–14. 2004. View Article : Google Scholar : PubMed/NCBI
22	Picketts DJ, Higgs DR, Bachoo S, Blake DJ, Quarrell OW and Gibbons RJ: ATRX encodes a novel member of the SNF2 family of proteins: Mutations point to a common mechanism underlying the ATR-X syndrome. Hum Mol Genet. 5:1899–1907. 1996. View Article : Google Scholar : PubMed/NCBI
23	Villard L, Gecz J, Mattéi JF, Fontés M, Saugier-Veber P, Munnich A and Lyonnet S: XNP mutation in a large family with Juberg-Marsidi syndrome. Nat Genet. 12:359–360. 1996. View Article : Google Scholar : PubMed/NCBI
24	Wong LH, McGhie JD, Sim M, Anderson MA, Ahn S, Hannan RD, George AJ, Morgan KA, Mann JR and Choo KH: ATRX interacts with H3.3 in maintaining telomere structural integrity in pluripotent embryonic stem cells. Genome Res. 20:351–360. 2010. View Article : Google Scholar : PubMed/NCBI
25	Villard L, Fontès M, Adès LC and Gecz J: Identification of a mutation in the XNP/ATR-X gene in a family reported as Smith-Fineman-Myers syndrome. Am J Med Genet. 91:83–85. 2000. View Article : Google Scholar : PubMed/NCBI
26	Abidi F, Schwartz CE, Carpenter NJ, Villard L, Fontes M and Curtis M: Carpenter-Waziri syndrome results from a mutation in XNP. Am J Med Genet. 85:249–251. 1999. View Article : Google Scholar : PubMed/NCBI
27	Qian X, Li J, Xu S, Wan Y, Li Y, Jiang Y, Zhao H, Zhou Y, Liao J, Liu H, et al: Prenatal exposure to phthalates and neurocognitive development in children at two years of age. Environ Int. 131:1050232019. View Article : Google Scholar : PubMed/NCBI
28	Guion-Almeida ML, Tabith A Jr, Kokitsu-Nakata NM and Zechi RM: Smith-Fineman-Myers syndrome in apparently monozygotic twins. Am J Med Genet. 79:205–208. 1998. View Article : Google Scholar : PubMed/NCBI
29	Budny B, Badura-Stronka M, Materna-Kiryluk A, Tzschach A, Raynaud M, Latos-Bielenska A and Ropers HH: Novel missense mutations in the ubiquitination-related gene UBE2A cause a recognizable X-linked mental retardation syndrome. Clin Genet. 77:541–551. 2010. View Article : Google Scholar : PubMed/NCBI
30	Giannandrea M, Bianchi V, Mignogna ML, Sirri A, Carrabino S, D'Elia E, Vecellio M, Russo S, Cogliati F, Larizza L, et al: Mutations in the small GTPase gene RAB39B are responsible for X-linked mental retardation associated with autism, epilepsy, and macrocephaly. Am J Hum Genet. 86:185–195. 2010. View Article : Google Scholar : PubMed/NCBI
31	Huo L, Teng Z, Wang H and Liu X: A novel splice site mutation in AP1S2 gene for X-linked mental retardation in a Chinese pedigree and literature review. Brain Behav. 9:e012212019. View Article : Google Scholar : PubMed/NCBI
32	Dyer MA, Qadeer ZA, Valle-Garcia D and Bernstein E: ATRX and DAXX: Mechanisms and mutations. Cold Spring Harb Perspect Med. 7(pii): a0265672017. View Article : Google Scholar : PubMed/NCBI
33	Haase S, Garcia-Fabiani MB, Carney S, Altshuler D, Núñez FJ, Méndez FM, Núñez F, Lowenstein PR and Castro MG: Mutant ATRX: Uncovering a new therapeutic target for glioma. Expert Opin Ther Targets. 22:599–613. 2018. View Article : Google Scholar : PubMed/NCBI
34	Gibbons RJ, Bachoo S, Picketts DJ, Aftimos S, Asenbauer B, Bergoffen J, Berry SA, Dahl N, Fryer A, Keppler K, et al: Mutations in transcriptional regulator ATRX establish the functional significance of a PHD-like domain. Nat Genet. 17:146–148. 1997. View Article : Google Scholar : PubMed/NCBI
35	Nandakumar P, Mansouri A and Das S: The role of ATRX in glioma biology. Front Oncol. 7:2362017. View Article : Google Scholar : PubMed/NCBI
36	Juhasz S, Elbakry A, Mathes A and Löbrich M: ATRX promotes DNA repair synthesis and sister chromatid exchange during homologous recombination. Mol Cell. 71:11–24.e7. 2018. View Article : Google Scholar : PubMed/NCBI
37	Badens C, Lacoste C, Philip N, Martini N, Courrier S, Giuliano F, Verloes A, Munnich A, Leheup B, Burglen L, et al: Mutations in PHD-like domain of the ATRX gene correlate with severe psychomotor impairment and severe urogenital abnormalities in patients with ATRX syndrome. Clin Genet. 70:57–62. 2006. View Article : Google Scholar : PubMed/NCBI
38	Ng SB, Buckingham KJ, Lee C, Bigham AW, Tabor HK, Dent KM, Huff CD, Shannon PT, Jabs EW, Nickerson DA, et al: Exome sequencing identifies the cause of a mendelian disorder. Nat Genet. 42:30–35. 2009. View Article : Google Scholar : PubMed/NCBI