An atypical case of neuronal ceroid lipofuscinosis with co-inheritance of a variably penetrant POLG1 mutation

BMC Medical Genetics

Katherine B Sims¹  Susan L Cotman¹  Rosemary Barone²  Winnie Xin¹  John F Staropoli³ 

[1] Center for Human Genetic Research, 185 Cambridge Street, Boston, MA, 02114, USA;Neurogenetics DNA Diagnostic Laboratory, Center for Human Genetic Research, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA, 02114, USA;Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA, 02114, USA

关键词: Oxidative phosphorylation;    mtDNA depletion;    POLG1;    CLN5;    Neuronal ceroid lipofuscinosis;   

Others  :  1177844
DOI  :  10.1186/1471-2350-13-50

 received in 2011-06-29, accepted in 2012-06-18,  发布年份 2012

【 摘 要 】

Background

The neuronal ceroid lipofuscinoses (NCLs, or Batten disease) comprise the most common Mendelian form of childhood-onset neurodegeneration, but the functions of the known underlying gene products remain poorly understood. The clinical heterogeneity of these disorders may shed light on genetic interactors that modify disease onset and progression.

Case presentation

We describe a proband with congenital hypotonia and an atypical form of infantile-onset, biopsy-proven NCL. Pathologic and molecular work-up of this patient identified CLN5 mutations as well as a mutation―previously described as incompletely penetrant or a variant of unknown significance―in POLG1, a nuclear gene essential for maintenance of mitochondrial DNA (mtDNA) copy number. The congenital presentation of this patient is far earlier than that described for either CLN5 patients or affected carriers of the POLG1 variant (c.1550 G > T, p.Gly517Val). Assessment of relative mtDNA copy number and mitochondrial membrane potential in the proband and control subjects suggested a pathogenic effect of the POLG1 change as well as a possible functional interaction with CLN5 mutations.

Conclusions

These findings suggest that an incompletely penetrant variant in POLG1 may modify the clinical phenotype in a case of CLN5 and are consistent with emerging evidence of interactions between NCL-related genes and mitochondrial physiology.

【 授权许可】

   
2012 Staropoli et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Jalanko A, Braulke T: Neuronal ceroid lipofuscinoses. Biochim Biophys Acta 2009, 1793:697-709.
• [2]Cooper JD, Russell C, Mitchison HM: Progress towards understanding disease mechanisms in small vertebrate models of neuronal ceroid lipofuscinosis. Biochim Biophys Acta 2006, 1762:873-889.
• [3]Pearce DA: Experimental models of NCL: the yeast model. Adv Genet 2001, 45:205-216.
• [4]Phillips SN, Muzaffar N, Codlin S, Korey CA, Taschner PE, de Voer G, Mole SE, Pearce DA: Characterizing pathogenic processes in Batten disease: use of small eukaryotic model systems. Biochim Biophys Acta 2006, 1762:906-919.
• [5]Palmer DN, Fearnley IM, Walker JE, Hall NA, Lake BD, Wolfe LS, Haltia M, Martinus RD, Jolly RD: Mitochondrial ATP synthase subunit c storage in the ceroid-lipofuscinoses (Batten disease). Am J Med Genet 1992, 42:561-567.
• [6]Fossale E, Wolf P, Espinola JA, Lubicz-Nawrocka T, Teed AM, Gao H, Rigamonti D, Cattaneo E, MacDonald ME, Cotman SL: Membrane trafficking and mitochondrial abnormalities precede subunit c deposition in a cerebellar cell model of juvenile neuronal ceroid lipofuscinosis. BMC Neurosci 2004, 5:57. BioMed Central Full Text
• [7]Cao Y, Staropoli JF, Biswas S, Espinola JA, Macdonald ME, Lee JM, Cotman SL: Distinct early molecular responses to mutations causing vLINCL and JNCL presage ATP synthase subunit C accumulation in cerebellar cells. PLoS One 2011, 6:e17118.
• [8]Noskova L, Stranecky V, Hartmannova H, Pristoupilova A, Baresova V, Ivanek R, Hulkova H, Jahnova H, van der Zee J, Staropoli JF, et al.: Mutations in DNAJC5, Encoding Cysteine-String Protein Alpha, Cause Autosomal-Dominant Adult-Onset Neuronal Ceroid Lipofuscinosis. Am J Hum Genet 2011, 89:241-252.
• [9]Xiao Q, Hartzell HC, Yu K: Bestrophins and retinopathies. Pflugers Arch 2010, 460:559-569.
• [10]Xin W, Mullen TE, Kiely R, Min J, Feng X, Cao Y, O'Malley L, Shen Y, Chu-Shore C, Mole SE, et al.: CLN5 mutations are frequent in juvenile and late-onset non-Finnish patients with NCL. Neurology 2010, 74:565-571.
• [11]UCSC: Genome Bioinformatics. [http://genome.ucsc.edu/ webcite]
• [12]Liou CW, Lin TK, Chen JB, Tiao MM, Weng SW, Chen SD, Chuang YC, Chuang JH, Wang PW: Association between a common mitochondrial DNA D-loop polycytosine variant and alteration of mitochondrial copy number in human peripheral blood cells. J Med Genet 2010, 47:723-728.
• [13]Siintola E, Partanen S, Stromme P, Haapanen A, Haltia M, Maehlen J, Lehesjoki AE, Tyynela J: Cathepsin D deficiency underlies congenital human neuronal ceroid-lipofuscinosis. Brain 2006, 129:1438-1445.
• [14]NHLBI: Exome Sequencing Project (ESP). Exome Variant Server; [http://evs.gs.washington.edu/EVS/ webcite]
• [15]Copeland WC: The mitochondrial DNA polymerase in health and disease. Subcell Biochem 2010, 50:211-222.
• [16]Vermulst M, Wanagat J, Kujoth GC, Bielas JH, Rabinovitch PS, Prolla TA, Loeb LA: DNA deletions and clonal mutations drive premature aging in mitochondrial mutator mice. Nat Genet 2008, 40:392-394.
• [17]Spelbrink JN, Toivonen JM, Hakkaart GA, Kurkela JM, Cooper HM, Lehtinen SK, Lecrenier N, Back JW, Speijer D, Foury F, Jacobs HT: In vivo functional analysis of the human mitochondrial DNA polymerase POLG expressed in cultured human cells. J Biol Chem 2000, 275:24818-24828.
• [18]Cohen BH, Naviaux RK: The clinical diagnosis of POLG disease and other mitochondrial DNA depletion disorders. Methods 2010, 51:364-373.
• [19]Wong LJ, Naviaux RK, Brunetti-Pierri N, Zhang Q, Schmitt ES, Truong C, Milone M, Cohen BH, Wical B, Ganesh J, et al.: Molecular and clinical genetics of mitochondrial diseases due to POLG mutations. Hum Mutat 2008, 29:E150-E172.
• [20]Horvath R, Hudson G, Ferrari G, Futterer N, Ahola S, Lamantea E, Prokisch H, Lochmuller H, McFarland R, Ramesh V, et al.: Phenotypic spectrum associated with mutations of the mitochondrial polymerase gamma gene. Brain 2006, 129:1674-1684.
• [21]Burusnukul P, de los Reyes EC: Phenotypic variations in 3 children with POLG1 mutations. J Child Neurol 2009, 24:482-486.
• [22]Jolly RD, Brown S, Das AM, Walkley SU: Mitochondrial dysfunction in the neuronal ceroid-lipofuscinoses (Batten disease). Neurochem Int 2002, 40:565-571.
• [23]Schulz A, Dhar S, Rylova S, Dbaibo G, Alroy J, Hagel C, Artacho I, Kohlschutter A, Lin S, Boustany RM: Impaired cell adhesion and apoptosis in a novel CLN9 Batten disease variant. Ann Neurol 2004, 56:342-350.
• [24]El Haddad S, Khoury M, Daoud M, Kantar R, Ghanem S, Mousallem T, Alzate O, Meyer B, Boustany RM: CLN9, CLN5, CLN8 proteins and ceramide synthases [abstract]. 13th International Conference on Neuronal Ceroid Lipofuscinoses (Batten Disease), London; 2012. 28–31 March 2012
• [25]Pezzini F, Gismondi F, Tessa A, Tonin P, Carrozzo R, Mole SE, Santorelli FM, Simonati A: Involvement of the mitochondrial compartment in human NCL fibroblasts. Biochem Biophys Res Commun 2011, 416:159-164.
• [26]Aharon-Peretz J, Rosenbaum H, Gershoni-Baruch R: Mutations in the glucocerebrosidase gene and Parkinson's disease in Ashkenazi Jews. N Engl J Med 2004, 351:1972-1977.
• [27]Davidzon G, Greene P, Mancuso M, Klos KJ, Ahlskog JE, Hirano M, DiMauro S: Early-onset familial parkinsonism due to POLG mutations. Ann Neurol 2006, 59:859-862.
• [28]Hudson G, Schaefer AM, Taylor RW, Tiangyou W, Gibson A, Venables G, Griffiths P, Burn DJ, Turnbull DM, Chinnery PF: Mutation of the linker region of the polymerase gamma-1 (POLG1) gene associated with progressive external ophthalmoplegia and Parkinsonism. Arch Neurol 2007, 64:553-557.
• [29]Tyynismaa H, Mjosund KP, Wanrooij S, Lappalainen I, Ylikallio E, Jalanko A, Spelbrink JN, Paetau A, Suomalainen A: Mutant mitochondrial helicase Twinkle causes multiple mtDNA deletions and a late-onset mitochondrial disease in mice. Proc Natl Acad Sci U S A 2005, 102:17687-17692.
• [30]Trifunovic A, Wredenberg A, Falkenberg M, Spelbrink JN, Rovio AT, Bruder CE, Bohlooly YM, Gidlof S, Oldfors A, Wibom R, et al.: Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 2004, 429:417-423.