Analyses of LMNA-negative juvenile progeroid cases confirms biallelic POLR3A mutations in Wiedemann-Rautenstrauch-like syndrome and expands the phenotypic spectrum of PYCR1 mutations

doi:10.1007/s00439-018-1957-1

. 2018 Dec;137(11-12):921-939.

doi: 10.1007/s00439-018-1957-1. Epub 2018 Nov 19.

Analyses of LMNA-negative juvenile progeroid cases confirms biallelic POLR3A mutations in Wiedemann-Rautenstrauch-like syndrome and expands the phenotypic spectrum of PYCR1 mutations

Davor Lessel¹, Ayse Bilge Ozel², Susan E Campbell³, Abdelkrim Saadi⁴, Martin F Arlt², Keisha Melodi McSweeney⁵, Vasilica Plaiasu⁶, Katalin Szakszon⁷, Anna Szőllős⁷, Cristina Rusu⁸, Armando J Rojas⁹, Jaime Lopez-Valdez¹⁰, Holger Thiele¹¹, Peter Nürnberg^{11

12

13}, Deborah A Nickerson¹⁴, Michael J Bamshad¹⁴, Jun Z Li², Christian Kubisch¹⁵, Thomas W Glover², Leslie B Gordon^{16

17}

Affiliations

¹ Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany. [email protected].
² Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
³ Center for Gerontology and Healthcare Research, Brown University, Providence, RI, USA.
⁴ Service de neurologie, CHU Ben Aknoun Alger, 2 route des deux Bassins, BenAknoun,, Algers, Algeria.
⁵ Oak Ridge Institute for Science and Education, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, 20993, Silver Spring, MD, USA.
⁶ Regional Center of Medical Genetics, Alessandrescu-Rusescu INSMC, Bucharest, Romania.
⁷ Department of Pediatrics, University of Debrecen, Debrecen, Hungary.
⁸ Department of Genetics, University Hospital Iasi, Iasi, Romania.
⁹ Instituto de Genética Humana, Facultad de Medicina, Pontificia Universidad Javeriana, Bogotá, Colombia.
¹⁰ Department of Genetics, Centenario Hospital Miguel Hidalgo, Aguascalientes, Mexico.
¹¹ Cologne Center for Genomics, University of Cologne, Cologne, Germany.
¹² Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
¹³ Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.
¹⁴ Department of Genome Sciences, University of Washington, Seattle, USA.
¹⁵ Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.
¹⁶ Warren Alpert Medical School of Brown University, Providence, RI, USA.
¹⁷ Department of Pediatrics, Division of Genetics, Hasbro Children's Hospital, Providence, RI, USA.

PMID: 30450527
PMCID: PMC6652186
DOI: 10.1007/s00439-018-1957-1

Analyses of LMNA-negative juvenile progeroid cases confirms biallelic POLR3A mutations in Wiedemann-Rautenstrauch-like syndrome and expands the phenotypic spectrum of PYCR1 mutations

Davor Lessel et al. Hum Genet. 2018 Dec.

. 2018 Dec;137(11-12):921-939.

doi: 10.1007/s00439-018-1957-1. Epub 2018 Nov 19.

Authors

Affiliations

¹ Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany. [email protected].
² Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
³ Center for Gerontology and Healthcare Research, Brown University, Providence, RI, USA.
⁴ Service de neurologie, CHU Ben Aknoun Alger, 2 route des deux Bassins, BenAknoun,, Algers, Algeria.
⁵ Oak Ridge Institute for Science and Education, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, 20993, Silver Spring, MD, USA.
⁶ Regional Center of Medical Genetics, Alessandrescu-Rusescu INSMC, Bucharest, Romania.
⁷ Department of Pediatrics, University of Debrecen, Debrecen, Hungary.
⁸ Department of Genetics, University Hospital Iasi, Iasi, Romania.
⁹ Instituto de Genética Humana, Facultad de Medicina, Pontificia Universidad Javeriana, Bogotá, Colombia.
¹⁰ Department of Genetics, Centenario Hospital Miguel Hidalgo, Aguascalientes, Mexico.
¹¹ Cologne Center for Genomics, University of Cologne, Cologne, Germany.
¹² Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
¹³ Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.
¹⁴ Department of Genome Sciences, University of Washington, Seattle, USA.
¹⁵ Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.
¹⁶ Warren Alpert Medical School of Brown University, Providence, RI, USA.
¹⁷ Department of Pediatrics, Division of Genetics, Hasbro Children's Hospital, Providence, RI, USA.

PMID: 30450527
PMCID: PMC6652186
DOI: 10.1007/s00439-018-1957-1

Abstract

Juvenile segmental progeroid syndromes are rare, heterogeneous disorders characterized by signs of premature aging affecting more than one tissue or organ starting in childhood. Hutchinson-Gilford progeria syndrome (HGPS), caused by a recurrent de novo synonymous LMNA mutation resulting in aberrant splicing and generation of a mutant product called progerin, is a prototypical example of such disorders. Here, we performed a joint collaborative study using massively parallel sequencing and targeted Sanger sequencing, aimed at delineating the underlying genetic cause of 14 previously undiagnosed, clinically heterogeneous, non-LMNA-associated juvenile progeroid patients. The molecular diagnosis was achieved in 11 of 14 cases (~ 79%). Furthermore, we firmly establish biallelic mutations in POLR3A as the genetic cause of a recognizable, neonatal, Wiedemann-Rautenstrauch-like progeroid syndrome. Thus, we suggest that POLR3A mutations are causal for a portion of under-diagnosed early-onset segmental progeroid syndromes. We additionally expand the clinical spectrum associated with PYCR1 mutations by showing that they can somewhat resemble HGPS in the first year of life. Moreover, our results lead to clinical reclassification in one single case. Our data emphasize the complex genetic and clinical heterogeneity underlying progeroid disorders.

Keywords: Hutchinson–Gilford progeria syndrome; Juvenile segmental progeroid syndrome; POLR3A; PYCR1; Wiedemann–Rautenstrauch progeroid syndrome.

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Conflict of interest statement

Conflict of interest The authors declare that they have no conflict of interest.

Figures

**Fig. 1**
Clinical characteristics of *POLR3A*-mutated individuals. Facial images of individual 1 at age 4 months, 1.5 years and 2 years and 10 months (a), individual 4 at the age of 1 year and 7 months, and 3 years (b), and individual 11 from the birth till 11 months (c)

**Fig. 2**
Clinical characteristics of *PYCR1*-mutated individuals. Facial images of individual 2 at 1.5 years and 9 years (a), individual 7 at the age of 10 months and 1.5 years (b), individual 13 at birth and 6 weeks (c), and individual 14 at 6 months (d)

**Fig. 3**
Clinical characteristics of *COL1A1*-mutated individual and the two unclassified juvenile progeroid individuals. Facial images of individual 3 bearing the de novo *COL1A1* mutation at age 8 months and 1 year (a), individual 8 at the age of 1 year and 3 years (b), and individual 9 at 13.5 years (c)

**Fig. 4**
*POLR3A* splicing defect caused by c.3337-5T > A mutation results in skipping of exon 26. Agarose gel electrophoresis of *POLR3A* RT-PCR products. The proband and father both carry the c.3337-5T > A mutation, resulting in a smaller band of ~ 287 bp corresponding to a cDNA missing exon 26 compared to the size of the wild-type band of ~ 380 bp (a). Sanger sequence traces of gel-extracted *POLR3A* RT-PCR products, demonstrating wild-type sequence of the larger band (top) and exon 26 skipping, both from individual 4 (bottom) (b)

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References

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1. Chong JX, McMillin MJ, Shively KM, Beck AE, Marvin CT, Armenteros JR, Buckingham KJ, Nkinsi NT, Boyle EA, Berry MN, Bocian M, Foulds N, Uzielli ML, Haldeman-Englert C, Hennekam RC, Kaplan P, Kline AD, Mercer CL, Nowaczyk MJ, Klein Wassink-Ruiter JS, McPherson EW, Moreno RA, Scheuerle AE, Shashi V, Stevens CA, Carey JC, Monteil A, Lory P, Tabor HK, Smith JD, Shendure J, Nickerson DA, Bamshad MJ, University of Washington Center for Mendelian G (2015) De novo mutations in NALCN cause a syndrome characterized by congenital contractures of the limbs and face, hypotonia, and developmental delay. Am J Hum Genet 96:462–473. 10.1016/ajhg.2015.01.003 - DOI - PMC - PubMed

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[1] Bernard G, Chouery E, Putorti ML, Tetreault M, Takanohashi A, Carosso G, Clement I, Boespflug-Tanguy O, Rodriguez D, Delague V, Abou Ghoch J, Jalkh N, Dorboz I, Fribourg S, Teich-mann M, Megarbane A, Schiffmann R, Vanderver A, Brais B (2011) Mutations of POLR3A encoding a catalytic subunit of RNA polymerase Pol III cause a recessive hypomyelinating leukodystrophy. Am J Hum Genet 89:415–423. https://doiorg/10.1016/j.ajhg.2011.07.014 - DOI - PMC - PubMed

[2] Bernard G, Chouery E, Putorti ML, Tetreault M, Takanohashi A, Carosso G, Clement I, Boespflug-Tanguy O, Rodriguez D, Delague V, Abou Ghoch J, Jalkh N, Dorboz I, Fribourg S, Teich-mann M, Megarbane A, Schiffmann R, Vanderver A, Brais B (2011) Mutations of POLR3A encoding a catalytic subunit of RNA polymerase Pol III cause a recessive hypomyelinating leukodystrophy. Am J Hum Genet 89:415–423. https://doiorg/10.1016/j.ajhg.2011.07.014 - DOI - PMC - PubMed

[3] Byers PH (1989) Inherited disorders of collagen gene structure and expression. Am J Med Genet 34:72–80. 10.1002/ajmg.1320340114 - DOI - PubMed

[4] Byers PH (1989) Inherited disorders of collagen gene structure and expression. Am J Med Genet 34:72–80. 10.1002/ajmg.1320340114 - DOI - PubMed

[5] Byers PH, Duvic M, Atkinson M, Robinow M, Smith LT, Krane SM, Greally MT, Ludman M, Matalon R, Pauker S, Quanbeck D, Schwarze U (1997) Ehlers-Danlos syndrome type VIIA and VIIB result from splice-junction mutations or genomic deletions that involve exon 6 in the COL1A1 and COL1A2 genes of type I collagen. Am J Med Genet 72:94–105 - PubMed

[6] Byers PH, Duvic M, Atkinson M, Robinow M, Smith LT, Krane SM, Greally MT, Ludman M, Matalon R, Pauker S, Quanbeck D, Schwarze U (1997) Ehlers-Danlos syndrome type VIIA and VIIB result from splice-junction mutations or genomic deletions that involve exon 6 in the COL1A1 and COL1A2 genes of type I collagen. Am J Med Genet 72:94–105 - PubMed

[7] Chen L, Lee L, Kudlow BA, Dos Santos HG, Sletvold O, Shafeghati Y, Botha EG, Garg A, Hanson NB, Martin GM, Mian IS, Kennedy BK, Oshima J (2003) LMNA mutations in atypical Werner’s syndrome. Lancet 362:440–445. 10.1016/S01406736(03)14069-X - DOI - PubMed

[8] Chen L, Lee L, Kudlow BA, Dos Santos HG, Sletvold O, Shafeghati Y, Botha EG, Garg A, Hanson NB, Martin GM, Mian IS, Kennedy BK, Oshima J (2003) LMNA mutations in atypical Werner’s syndrome. Lancet 362:440–445. 10.1016/S01406736(03)14069-X - DOI - PubMed

[9] Chong JX, McMillin MJ, Shively KM, Beck AE, Marvin CT, Armenteros JR, Buckingham KJ, Nkinsi NT, Boyle EA, Berry MN, Bocian M, Foulds N, Uzielli ML, Haldeman-Englert C, Hennekam RC, Kaplan P, Kline AD, Mercer CL, Nowaczyk MJ, Klein Wassink-Ruiter JS, McPherson EW, Moreno RA, Scheuerle AE, Shashi V, Stevens CA, Carey JC, Monteil A, Lory P, Tabor HK, Smith JD, Shendure J, Nickerson DA, Bamshad MJ, University of Washington Center for Mendelian G (2015) De novo mutations in NALCN cause a syndrome characterized by congenital contractures of the limbs and face, hypotonia, and developmental delay. Am J Hum Genet 96:462–473. 10.1016/ajhg.2015.01.003 - DOI - PMC - PubMed

[10] Chong JX, McMillin MJ, Shively KM, Beck AE, Marvin CT, Armenteros JR, Buckingham KJ, Nkinsi NT, Boyle EA, Berry MN, Bocian M, Foulds N, Uzielli ML, Haldeman-Englert C, Hennekam RC, Kaplan P, Kline AD, Mercer CL, Nowaczyk MJ, Klein Wassink-Ruiter JS, McPherson EW, Moreno RA, Scheuerle AE, Shashi V, Stevens CA, Carey JC, Monteil A, Lory P, Tabor HK, Smith JD, Shendure J, Nickerson DA, Bamshad MJ, University of Washington Center for Mendelian G (2015) De novo mutations in NALCN cause a syndrome characterized by congenital contractures of the limbs and face, hypotonia, and developmental delay. Am J Hum Genet 96:462–473. 10.1016/ajhg.2015.01.003 - DOI - PMC - PubMed

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Analyses of LMNA-negative juvenile progeroid cases confirms biallelic POLR3A mutations in Wiedemann-Rautenstrauch-like syndrome and expands the phenotypic spectrum of PYCR1 mutations

Affiliations

Analyses of LMNA-negative juvenile progeroid cases confirms biallelic POLR3A mutations in Wiedemann-Rautenstrauch-like syndrome and expands the phenotypic spectrum of PYCR1 mutations

Authors

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Abstract

Conflict of interest statement

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