Mutations in MFSD8/CLN7 are a frequent cause of variant-late infantile neuronal ceroid lipofuscinosis

Abstract

ABSTRACT:The neuronal ceroid lipofuscinoses (NCL) are a group of genetically heterogeneous neurodegenerative disorders. The recent identification of the MFSD8/CLN7 gene in a variant-late infantile form of NCL (v-LINCL) in affected children from Turkey prompted us to examine the relative frequency of variants in this gene in Italian patients with v-LINCL. We identified nine children harboring 11 different mutations in MFSD8/CLN7. Ten mutations were novel and included three nonsense (p.Arg35Stop, p.Glu381Stop, p.Arg482Stop), four missense (p.Met1Thr, p.Gly52Arg, p.Thr294Lys, p.Pro447Leu), two splice site mutations (c.863+3_4insT, c.863+1G>C), and a 17-bp deletion predicting a frameshift and premature protein truncation (c.627_643del17/p.Met209IlefsX3). The clinical phenotype, which was similar to that of the Turkish v-LINCL cases, was not influenced by type and location of the mutation nor the length of the predicted residual gene product. As well as identifying novel variants in MFSD8/CLN7, this study contributes to a better molecular characterization of Italian NCL cases, and will facilitate medical genetic counseling in such families. The existence of a subset of v-LINCL cases without mutations in any of the known NCL genes suggests further genetic heterogeneity.

Retinal Degeneration in Mice Deficient in the Lysosomal Membrane Protein CLN7

“…Retinal degeneration leading to visual impairment and ultimately blindness during the course of the disease has been reported as a typical neurologic symptom in patients with CLN7 with vLINCL phenotype, 7,8,[15][16][17][18][19]21,22,45 in a naturally occurring CLN7 canine model, 46 and in a hypomorphic mouse model of CLN7 disease. 11 However, precise information about the onset and progression of the retinal pathology, the affected retinal layers and retinal cell types, and the biochemical alterations associated with CLN7 disease, vLINCL phenotype, are largely missing.…”

“…7,15 With only a few exceptions, the more than 35 different mutations in the CLN7/ iovs.arvojournals.org j ISSN: 1552-5783 MFSD8 gene identified in patients with CLN7 cause vLINCL and, based on the relatively uniform clinical manifestation, are thought to result in a complete loss of protein function (http:// www.ucl.ac.uk/ncl). 4,7,8,[16][17][18][19][20][21][22] In addition to the mutations causing vLINCL, a missense mutation in CLN7/MFSD8 affecting a residue located in a cytosolic loop of CLN7 (p.Ala157Pro) was reported to cause a milder disease course with juvenile onset. 18 Furthermore, compound heterozygous variants in CLN7/MFSD8 have been identified in patients presenting with autosomal recessive macular dystrophy with central cone involvement but lacking the characteristic hallmarks and severe neurologic symptoms of patients with CLN7 with the vLINCL phenotype (MIM 616170).…”

Myoclonic Epilepsy in Lysosomal Storage Disorders

“…Mutations in CLN7 gene have been initially described in Turkish patients (Siintola et al, 2007) and therefore it has been considered the Turkish variant late infantile NCL. However, it has been recently shown that CLN7 defects are geographically widespread (Aiello et al, 2009;Aldahmesh et al, 2009;Stogmann et al, 2009;Kousi et al, 2009). The missense mutation c.881C>A (p.T294K) was found in most patients of Romany origin previously studied by Elleder et al (Elleder et al, 1997).…”

Therapeutic Approaches to the Challenge of Neuronal Ceroid Lipofuscinoses

“…It is now recognized that mutations in all genes are distributed across many countries, albeit with higher incidence in some ethnic groups due to founder effects. Among the many recognized variants of NCL human forms (recent reviews in [3,6,11]), eight causal genes have been identified: CLN10/CTSD [12][13][14], CLN1/PPT1 [3,6,[15][16][17][18], CLN2/TPP1 [6,[18][19][20][21], CLN3 [22][23][24][25], CLN5 [26][27][28][29][30], CLN6 [31][32][33][34], CLN7/ MFSD8 [35][36][37][38][39], CLN8 [40][41][42]. The genes CLCN6 [43], and CLCN7 [44], and possibly SGSH [45], may also contribute to rare forms of NCL.…”

“…CLN7 disease-This late infantile variant CLN7 disease was originally observed in Turkish families, but is now recognized to have a wider distribution including Italy [39], Arabia Saudi [38], Czech Republic [36], Austria [37], India [68], among others. It is caused by mutations in the CLN7 gene (properly termed MFSD8) coding for a putative lysosomal transporter protein.…”