Mucolipidosis type IV: NovelMCOLN1 mutations in Jewish and non-Jewish patients and the frequency of the disease in the Ashkenazi Jewish population

Abstract

The gene MCOLN1 is mutated in Mucolipidosis type IV (MLIV), a neurodegenerative, recessive, lysosomal storage disorder. The disease is found in relatively high frequency among Ashkenazi Jews due to two founder mutations that comprise 95% of the MLIV alleles in this population [Bargal et al., 2000]. In this report we complete the mutation analysis of Jewish and non-Jewish MLIV patients whose DNA were available to us. Four novel mutations were identified in the MCOLN1 gene of severely affected patients: two missense, T232P and F465L; a nonsense, R322X; and an 11-bp insertion in exon 12. The nonsense mutation (R322X) was identified in two unrelated patients with different haplotypes in the MCOLN1 chromosomal region, indicating a mutation hotspot in this CpG site. An in-frame deletion (F408del) was identified in a patient with unusual mild psychomotor retardation. The frequency of MLIV in the general Jewish Ashkenazi population was estimated in a sample of 2,000 anonymous, unrelated individuals assayed for the two founder mutations. This analysis indicated a heterozygotes frequency of about 1/100. A preferred nucleotide numbering system for MCOLN1 mutations is presented and the issue of a screening program for the detection of high-risk families in the Jewish Ashkenazi population is discussed.

Heteromultimeric TRPML channel assemblies play a crucial role in the regulation of cell viability models and starvation-induced autophagy

“…The TRPML1(F465L) mutation displays autosomal recessive inheritance in humans (Bargal et al, 2001), meaning that the dominant-negative behavior, demonstrated in our assay of SIA, should not necessarily be expected even when the channel is overexpressed in cells. As a result, we sought to further characterize the dominant-negative properties of TRPML1(F465L) in our cell viability assays (described in Fig.…”

“…Although a thorough clinical and phenotypic assessment has not been performed with carriers of the F465L mutation in TRPML1, the mutation originally presented with apparent autosomal recessive inheritance in the family where the mutation was identified (Bargal et al, 2001). On the other hand, we have seen that this mutation accrues dominant-negative properties to the TRPML1 channel, and it should also be noted that heterozygote carriers of MLIVassociated mutations, in general, exhibit slightly more lysosomal inclusions than normal in electron micrographs (our unpublished observations).…”

“…Accordingly, we tested SIA in cells expressing the known channel-impaired TRPML1(F465L) mutant (Dong et al, 2008;Kiselyov et al, 2005). The F465L missense mutation in TRPML1 was first described in compound heterozygosity with a TRPML1-null allele in an MLIV patient (Bargal et al, 2001;Kiselyov et al, 2005). In addition, this mutation does not interfere with the ability of TRPML1 to physically interact with both WT-TRPMLs (supplementary material Fig.…”

Mucolipidosis Type IV: The Effect of Increased Lysosomal pH on the Abnormal Lysosomal Storage

“…Cultured skin fibroblasts from two patients with MLIV were used in this study. The first patient, AJ is severely affected, was found to be a compound heterozygote for the AJ founder mutation del EX1-EX7 (14,17) and c.1210insT. The second patient, a mild patient, also AJ, bearing two MCOLN1 mutations, the major AJ founder mutation and an in-frame amino acid deletion (⌬F408, c.1221-1223 del CTT).…”

TRP channels as potential drug targets

“…Two defined mutations in the MCOLN1 gene are found in about 95% of patients of the Ashkenazi Jewish alleles (Bargal et al, 2001;Slaugenhaupt, 2002). Whether these mutations affect function, trafficking or regulation of the MCOLN1 protein is not known.…”