Mutations in PURA cause profound neonatal hypotonia, seizures, and encephalopathy in 5q31.3 microdeletion syndrome

doi:10.1016/j.ajhg.2014.09.014

. 2014 Nov 6;95(5):579-83.

doi: 10.1016/j.ajhg.2014.09.014. Epub 2014 Oct 16.

Mutations in PURA cause profound neonatal hypotonia, seizures, and encephalopathy in 5q31.3 microdeletion syndrome

Seema R Lalani¹, Jing Zhang², Christian P Schaaf³, Chester W Brown⁴, Pilar Magoulas², Anne Chun-Hui Tsai⁵, Areeg El-Gharbawy⁶, Klaas J Wierenga⁷, Dennis Bartholomew⁸, Chin-To Fong⁹, Tina Barbaro-Dieber¹⁰, Mary K Kukolich¹⁰, Lindsay C Burrage², Elise Austin², Kory Keller⁵, Matthew Pastore⁸, Fabio Fernandez¹¹, Timothy Lotze¹¹, Angus Wilfong¹¹, Gabriela Purcarin¹², Wenmiao Zhu², William J Craigen², Marianne McGuire², Mahim Jain², Erin Cooney², Mahshid Azamian², Matthew N Bainbridge¹³, Donna M Muzny¹⁴, Eric Boerwinkle¹⁵, Richard E Person¹⁶, Zhiyv Niu¹⁶, Christine M Eng¹⁶, James R Lupski¹⁷, Richard A Gibbs¹⁸, Arthur L Beaudet², Yaping Yang¹⁶, Meng C Wang¹⁹, Fan Xia²⁰

Affiliations

¹ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: seemal@bcm.edu.
² Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
³ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.
⁴ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
⁵ Department of Molecular and Medical Genetics, Oregon Health and Sciences University, Portland, OR 97239, USA.
⁶ Department of Pediatrics and Division of Medical Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
⁷ Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
⁸ Division of Molecular and Human Genetics, Nationwide Children's Hospital, Columbus, OH 43205, USA.
⁹ Clinic of Inherited Metabolic Disease, University of Rochester Medical Center, Rochester, NY 14642, USA.
¹⁰ Clinical Genetics, Cook Children's Hospital, Fort Worth, TX 76102, USA.
¹¹ Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
¹² Department of Neurology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
¹³ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
¹⁴ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Whole Genome Laboratory, Baylor College of Medicine, Houston, TX 77030, USA.
¹⁵ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Human Genetics Center, University of Texas Health Science Center, Houston, TX 77030, USA.
¹⁶ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Whole Genome Laboratory, Baylor College of Medicine, Houston, TX 77030, USA.
¹⁷ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Texas Children's Hospital, Houston, TX 77030, USA.
¹⁸ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
¹⁹ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA.
²⁰ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Whole Genome Laboratory, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: fxia@bcm.edu.

PMID: 25439098
PMCID: PMC4225583
DOI: 10.1016/j.ajhg.2014.09.014

Mutations in PURA cause profound neonatal hypotonia, seizures, and encephalopathy in 5q31.3 microdeletion syndrome

Seema R Lalani et al. Am J Hum Genet. 2014.

. 2014 Nov 6;95(5):579-83.

doi: 10.1016/j.ajhg.2014.09.014. Epub 2014 Oct 16.

Authors

Affiliations

¹ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: seemal@bcm.edu.
² Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
³ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.
⁴ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
⁵ Department of Molecular and Medical Genetics, Oregon Health and Sciences University, Portland, OR 97239, USA.
⁶ Department of Pediatrics and Division of Medical Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
⁷ Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
⁸ Division of Molecular and Human Genetics, Nationwide Children's Hospital, Columbus, OH 43205, USA.
⁹ Clinic of Inherited Metabolic Disease, University of Rochester Medical Center, Rochester, NY 14642, USA.
¹⁰ Clinical Genetics, Cook Children's Hospital, Fort Worth, TX 76102, USA.
¹¹ Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
¹² Department of Neurology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
¹³ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
¹⁴ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Whole Genome Laboratory, Baylor College of Medicine, Houston, TX 77030, USA.
¹⁵ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Human Genetics Center, University of Texas Health Science Center, Houston, TX 77030, USA.
¹⁶ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Whole Genome Laboratory, Baylor College of Medicine, Houston, TX 77030, USA.
¹⁷ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Texas Children's Hospital, Houston, TX 77030, USA.
¹⁸ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
¹⁹ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA.
²⁰ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Whole Genome Laboratory, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: fxia@bcm.edu.

PMID: 25439098
PMCID: PMC4225583
DOI: 10.1016/j.ajhg.2014.09.014

Abstract

5q31.3 microdeletion syndrome is characterized by neonatal hypotonia, encephalopathy with or without epilepsy, and severe developmental delay, and the minimal critical deletion interval harbors three genes. We describe 11 individuals with clinical features of 5q31.3 microdeletion syndrome and de novo mutations in PURA, encoding transcriptional activator protein Pur-α, within the critical region. These data implicate causative PURA mutations responsible for the severe neurological phenotypes observed in this syndrome.

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Figures

**Figure 1**
*PURA* Mutations in the Affected Human Subjects and Functions of the *PURA* Ortholog in Model System *C. elegans* (A) *PURA* is located in chromosomal region 5q31.2 (according to the UCSC Genome Browser). A single exon (blue) encodes a protein with three PUR motifs, as shown in green. On the protein diagram, missense and in-frame-deletion mutations are brown, and the truncating mutations are shown in red. (B) Six subjects with de novo *PURA* mutations are shown. The craniofacial features are mainly characterized by myopathic facies. For whom clinical photographs are shown, informed consent specifically agreeing to publish these photographs in medical publications was obtained. (C) DNA staining in the germline of a wild-type *C. elegans* animal. Yellow dashed lines indicate differentiated oocytes. (D) Oocytes were absent in the *plp-1*-mutant animal with smaller gonads. Wild-type (N2) and RB1711 (*plp-1(ok2155)IV*) animals were obtained from the Caenorhabditis Genetics Center. *C. elegans* were grown on standard nematode growth media plates (containing 5 mg/l cholesterol) with *E. coli* OP50 at 25°C according to standard protocols. DAPI staining was performed at room temperature. The germline was dissected out from young adult worms. (E) Average speed of individual worm movement (wild-type n = 14, *plp-1* n = 12). The p value was obtained by a one-tailed Student’s t test. Error bars in the scattered dot plot represent the mean and the SEM. Spontaneous movement of age-synchronized worms on standard worm plates was recorded for 15 s with an SMZ1500 stereo microscope (Nikon) connected to a C11440 camera (Hamamatsu). Individual worms were tracked with NIS Elements AR 2D tracking imaging software (Nikon), and the average velocity (μm/s) was calculated. Representative recording of wild-type worms and *plp-1* mutants are shown in Movies S1 and S2, respectively.

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References

1. Shimojima K., Isidor B., Le Caignec C., Kondo A., Sakata S., Ohno K., Yamamoto T. A new microdeletion syndrome of 5q31.3 characterized by severe developmental delays, distinctive facial features, and delayed myelination. Am. J. Med. Genet. A. 2011;155A:732–736. - PubMed
1. Hosoki K., Ohta T., Natsume J., Imai S., Okumura A., Matsui T., Harada N., Bacino C.A., Scaglia F., Jones J.Y. Clinical phenotype and candidate genes for the 5q31.3 microdeletion syndrome. Am. J. Med. Genet. A. 2012;158A:1891–1896. - PubMed
1. Brown N., Burgess T., Forbes R., McGillivray G., Kornberg A., Mandelstam S., Stark Z. 5q31.3 Microdeletion syndrome: clinical and molecular characterization of two further cases. Am. J. Med. Genet. A. 2013;161A:2604–2608. - PubMed
1. Rosenfeld J.A., Drautz J.M., Clericuzio C.L., Cushing T., Raskin S., Martin J., Tervo R.C., Pitarque J.A., Nowak D.M., Karolak J.A. Deletions and duplications of developmental pathway genes in 5q31 contribute to abnormal phenotypes. Am. J. Med. Genet. A. 2011;155A:1906–1916. - PubMed
1. Yang Y., Muzny D.M., Reid J.G., Bainbridge M.N., Willis A., Ward P.A., Braxton A., Beuten J., Xia F., Niu Z. Clinical whole-exome sequencing for the diagnosis of mendelian disorders. N. Engl. J. Med. 2013;369:1502–1511. - PMC - PubMed

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[1] Shimojima K., Isidor B., Le Caignec C., Kondo A., Sakata S., Ohno K., Yamamoto T. A new microdeletion syndrome of 5q31.3 characterized by severe developmental delays, distinctive facial features, and delayed myelination. Am. J. Med. Genet. A. 2011;155A:732–736. - PubMed

[2] Shimojima K., Isidor B., Le Caignec C., Kondo A., Sakata S., Ohno K., Yamamoto T. A new microdeletion syndrome of 5q31.3 characterized by severe developmental delays, distinctive facial features, and delayed myelination. Am. J. Med. Genet. A. 2011;155A:732–736. - PubMed

[3] Hosoki K., Ohta T., Natsume J., Imai S., Okumura A., Matsui T., Harada N., Bacino C.A., Scaglia F., Jones J.Y. Clinical phenotype and candidate genes for the 5q31.3 microdeletion syndrome. Am. J. Med. Genet. A. 2012;158A:1891–1896. - PubMed

[4] Hosoki K., Ohta T., Natsume J., Imai S., Okumura A., Matsui T., Harada N., Bacino C.A., Scaglia F., Jones J.Y. Clinical phenotype and candidate genes for the 5q31.3 microdeletion syndrome. Am. J. Med. Genet. A. 2012;158A:1891–1896. - PubMed

[5] Brown N., Burgess T., Forbes R., McGillivray G., Kornberg A., Mandelstam S., Stark Z. 5q31.3 Microdeletion syndrome: clinical and molecular characterization of two further cases. Am. J. Med. Genet. A. 2013;161A:2604–2608. - PubMed

[6] Brown N., Burgess T., Forbes R., McGillivray G., Kornberg A., Mandelstam S., Stark Z. 5q31.3 Microdeletion syndrome: clinical and molecular characterization of two further cases. Am. J. Med. Genet. A. 2013;161A:2604–2608. - PubMed

[7] Rosenfeld J.A., Drautz J.M., Clericuzio C.L., Cushing T., Raskin S., Martin J., Tervo R.C., Pitarque J.A., Nowak D.M., Karolak J.A. Deletions and duplications of developmental pathway genes in 5q31 contribute to abnormal phenotypes. Am. J. Med. Genet. A. 2011;155A:1906–1916. - PubMed

[8] Rosenfeld J.A., Drautz J.M., Clericuzio C.L., Cushing T., Raskin S., Martin J., Tervo R.C., Pitarque J.A., Nowak D.M., Karolak J.A. Deletions and duplications of developmental pathway genes in 5q31 contribute to abnormal phenotypes. Am. J. Med. Genet. A. 2011;155A:1906–1916. - PubMed

[9] Yang Y., Muzny D.M., Reid J.G., Bainbridge M.N., Willis A., Ward P.A., Braxton A., Beuten J., Xia F., Niu Z. Clinical whole-exome sequencing for the diagnosis of mendelian disorders. N. Engl. J. Med. 2013;369:1502–1511. - PMC - PubMed

[10] Yang Y., Muzny D.M., Reid J.G., Bainbridge M.N., Willis A., Ward P.A., Braxton A., Beuten J., Xia F., Niu Z. Clinical whole-exome sequencing for the diagnosis of mendelian disorders. N. Engl. J. Med. 2013;369:1502–1511. - PMC - PubMed

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Mutations in PURA cause profound neonatal hypotonia, seizures, and encephalopathy in 5q31.3 microdeletion syndrome

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Mutations in PURA cause profound neonatal hypotonia, seizures, and encephalopathy in 5q31.3 microdeletion syndrome

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