Editing Primary familial brain calcification (section)

==Causes==

This condition can be inherited in an autosomal dominant or recessive fashion. Several genes have been associated with this condition.{{citation needed|date=December 2020}}

===Mutation===
A locus at 14q has been suggested, but no gene has been identified.<ref name="pmid10441584">{{cite journal |vauthors=Geschwind DH, Loginov M, Stern JM |title=Identification of a locus on chromosome 14q for idiopathic basal ganglia calcification (Fahr disease) |journal=Am. J. Hum. Genet. |volume=65 |issue=3 |pages=764–72 |date=September 1999 |pmid=10441584 |pmc=1377984 |doi=10.1086/302558 }}</ref> A second locus has been identified on chromosome 8<ref>{{cite journal  |vauthors=Dai X, Gao Y, Xu Z, etal |title=Identification of a novel genetic locus on chromosome 8p21.1-q11.23 for idiopathic basal ganglia calcification |journal=Am. J. Med. Genet. B Neuropsychiatr. Genet. |volume=153B |issue=7 |pages=1305–10 |date=October 2010 |pmid=20552677 |doi=10.1002/ajmg.b.31102 |s2cid=21165897 }}</ref> and a third has been reported on chromosome 2.<ref name=Volpato2009>{{cite journal  |vauthors=Volpato CB, De Grandi A, Buffone E, etal |title=2q37 as a susceptibility locus for idiopathic basal ganglia calcification (IBGC) in a large South Tyrolean family |journal=J. Mol. Neurosci. |volume=39 |issue=3 |pages=346–53 |date=November 2009 |pmid=19757205 |doi=10.1007/s12031-009-9287-3 |s2cid=23235853 }}</ref> This suggests there may be some [[genetic heterogeneity]] in this disease.<ref name=Oliveira2004>{{cite journal  |vauthors=Oliveira JR, Spiteri E, Sobrido MJ, etal |title=Genetic heterogeneity in familial idiopathic basal ganglia calcification (Fahr disease) |journal=Neurology |volume=63 |issue=11 |pages=2165–7 |date=December 2004 |pmid=15596772 |doi=10.1212/01.wnl.0000145601.88274.88|s2cid=22046680 |url=https://escholarship.org/uc/item/79v1w0dv }}</ref>

A mutation in the gene encoding the type III sodium dependent [[phosphate transporter]] 2 ([[SLC20A2]]) located on [[chromosome 8]] has been reported.<ref name=Wang2012>{{cite journal  |vauthors=Wang C, Li Y, Shi L, etal |title=Mutations in SLC20A2 link familial idiopathic basal ganglia calcification with phosphate homeostasis |journal=Nat. Genet. |volume=44 |issue=3 |pages=254–6 |date=March 2012 |pmid=22327515 |doi=10.1038/ng.1077 |s2cid=2515200 }}</ref> Biochemical evidence suggests that phosphate transport may be involved in this disease.{{citation needed|date=November 2020}}

Two other genes have been associated with this condition: [[PDGFB]] on [[chromosome 22]] and [[PDGFRB]] on [[chromosome 5]].<ref name=Westenberger2014>Westenberger A1, Klein C (2014) The genetics of primary familial brain calcifications. Curr Neurol Neurosci Rep 14(10):490 doi: 10.1007/s11910-014-0490-4</ref> These genes are biochemically linked: PDGFRB encodes the platelet-derived growth factor receptor β and PDGFB encodes the ligand of PDGF-Rβ. These genes are active during angiogenesis to recruit pericytes which suggests that alterations in the blood brain barrier may be involved in the pathogenesis of this condition.{{citation needed|date=November 2020}}

A fourth gene associated with this condition is [[XPR1]]. This gene is the long arm of located on [[chromosome 1]] (1q25.3).{{citation needed|date=December 2020}}

Another gene that has been associated with this condition is [[MYORG]].<ref name=Arkadir2018>Arkadir D, Lossos A, Rahat D, Abu Snineh M, Schueler-Furman O, Nitschke S, Minassian BA, Sadaka Y, Lerer I, Tabach Y, Meiner V (2018)  MYORG is associated with recessive primary familial brain calcification. Ann Clin Transl Neurol 6(1):106-113</ref><ref name=Yao2918>Yao XP, Cheng X, Wang C, Zhao M, Guo XX, Su HZ, Lai LL, Zou XH, Chen XJ, Zhao Y, Dong EL, Lu YQ, Wu S, Li X, Fan G, Yu H, Xu J, Wang N, Xiong ZQ, Chen WJ (2018) Biallelic Mutations in MYORG cause autosomal recessive primary familial brain calcification. Neuron 98(6):1116-1123</ref> This gene is located on the long arm of [[chromosome 9]] (9p13.3). This gene is associated with an autosomal recessive inheritance pattern in this condition.{{citation needed|date=November 2020}}

Another gene junctional adhesion molecule 2 ([[JAM2]]) has been associated with an autosomal recessive form of this condition.<ref name=Cen2019>Cen Z, Chen Y, Chen S, Wang H, Yang D, Zhang H, Wu H, Wang L, Tang S, Ye J, Shen J, Wang H, Fu F, Chen X, Xie F, Liu P, Xu X, Cao J, Cai P, Pan Q1,12, Li J, Yang W, Shan PF, Li Y, Liu JY, Zhang B, Luo W (2019) Biallelic loss-of-function mutations in JAM2 cause primary familial brain calcification. Brain</ref> 

The most recently found gene to be associated with PFBC is [[Nα-acetyltransferase 60]] (NAA60).<ref>{{Cite journal |last1=Chelban |first1=Viorica |last2=Aksnes |first2=Henriette |last3=Maroofian |first3=Reza |last4=LaMonica |first4=Lauren C. |last5=Seabra |first5=Luis |last6=Siggervåg |first6=Anette |last7=Devic |first7=Perrine |last8=Shamseldin |first8=Hanan E. |last9=Vandrovcova |first9=Jana |last10=Murphy |first10=David |last11=Richard |first11=Anne-Claire |last12=Quenez |first12=Olivier |last13=Bonnevalle |first13=Antoine |last14=Zanetti |first14=M. Natalia |last15=Kaiyrzhanov |first15=Rauan |date=2024-03-13 |title=Biallelic NAA60 variants with impaired N-terminal acetylation capacity cause autosomal recessive primary familial brain calcifications |journal=Nature Communications |language=en |volume=15 |issue=1 |page=2269 |doi=10.1038/s41467-024-46354-0 |issn=2041-1723 |pmc=10937998 |pmid=38480682|bibcode=2024NatCo..15.2269C }}</ref> NAA60 is a protein belonging to the family of N-terminal acetyltransferases (NATs), which catalyze the transfer of an acetyl group from acetyl-coenzyme A (Ac-CoA) to the N-terminus of proteins.<ref>{{Cite journal |last1=Aksnes |first1=Henriette |last2=Ree |first2=Rasmus |last3=Arnesen |first3=Thomas |date=2019 |title=Co-translational, Post-translational, and Non-catalytic Roles of N-Terminal Acetyltransferases |journal=Molecular Cell |language=en |volume=73 |issue=6 |pages=1097–1114 |doi=10.1016/j.molcel.2019.02.007 |pmc=6962057 |pmid=30878283}}</ref> NAA60 is specifically localized to the Golgi apparatus and can acetylate membrane proteins post-translationally that have cytosolic N-termini starting with methionine followed by hydrophobic- or amphipathic-type amino acids (ML-, MI-, MF-, MY-, and MK-).<ref>{{Cite journal |last1=Aksnes |first1=Henriette |last2=Van Damme |first2=Petra |last3=Goris |first3=Marianne |last4=Starheim |first4=Kristian K. |last5=Marie |first5=Michaël |last6=Støve |first6=Svein Isungset |last7=Hoel |first7=Camilla |last8=Kalvik |first8=Thomas Vikestad |last9=Hole |first9=Kristine |last10=Glomnes |first10=Nina |last11=Furnes |first11=Clemens |last12=Ljostveit |first12=Sonja |last13=Ziegler |first13=Mathias |last14=Niere |first14=Marc |last15=Gevaert |first15=Kris |date=2015 |title=An Organellar Nα-Acetyltransferase, Naa60, Acetylates Cytosolic N Termini of Transmembrane Proteins and Maintain Golgi Integrity |url=https://linkinghub.elsevier.com/retrieve/pii/S2211124715000789 |journal=Cell Reports |language=en |volume=10 |issue=8 |pages=1362–1374 |doi=10.1016/j.celrep.2015.01.053|pmid=25732826 |hdl=1956/10959 |hdl-access=free }}</ref><ref>{{Cite journal |last1=Støve |first1=Svein Isungset |last2=Magin |first2=Robert S. |last3=Foyn |first3=Håvard |last4=Haug |first4=Bengt Erik |last5=Marmorstein |first5=Ronen |last6=Arnesen |first6=Thomas |date=2016 |title=Crystal Structure of the Golgi-Associated Human Nα-Acetyltransferase 60 Reveals the Molecular Determinants for Substrate-Specific Acetylation |journal=Structure |language=en |volume=24 |issue=7 |pages=1044–1056 |doi=10.1016/j.str.2016.04.020 |pmc=4938767 |pmid=27320834}}</ref><ref>{{Cite journal |last1=Van Damme |first1=Petra |last2=Evjenth |first2=Rune |last3=Foyn |first3=Håvard |last4=Demeyer |first4=Kimberly |last5=De Bock |first5=Pieter-Jan |last6=Lillehaug |first6=Johan R. |last7=Vandekerckhove |first7=Joël |last8=Arnesen |first8=Thomas |last9=Gevaert |first9=Kris |date=2011 |title=Proteome-derived Peptide Libraries Allow Detailed Analysis of the Substrate Specificities of Nα-acetyltransferases and Point to hNaa10p as the Post-translational Actin Nα-acetyltransferase |journal=Molecular & Cellular Proteomics |language=en |volume=10 |issue=5 |pages=M110.004580 |doi=10.1074/mcp.M110.004580 |doi-access=free |pmc=3098586 |pmid=21383206}}</ref>