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PRUNE is crucial for normal brain development and mutated in microcephaly with neurodevelopmental impairment

View Article: PubMed Central - PubMed

ABSTRACT

Zollo et al. report that mutations in PRUNE1, a phosphoesterase superfamily molecule, underlie primary microcephaly and profound global developmental delay in four unrelated families from Oman, India, Iran and Italy. The study highlights a potential role for prune during microtubule polymerization, suggesting that prune syndrome may be a tubulinopathy.

No MeSH data available.


Family pedigrees, genotype and PRUNE mutation. Mutations in PRUNE1 detected in Omani (A); Iranian (B); Italian (C) and Indian (D) families. (E) Alignment of PRUNE amino acid sequence showing stringent conservation of the Asp30; Pro54; Asp106 and Arg297 residues. (F) 3D model of PRUNE showing the location and close proximity of the Asp30 and Arg297 amino acid residues.
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awx014-F1: Family pedigrees, genotype and PRUNE mutation. Mutations in PRUNE1 detected in Omani (A); Iranian (B); Italian (C) and Indian (D) families. (E) Alignment of PRUNE amino acid sequence showing stringent conservation of the Asp30; Pro54; Asp106 and Arg297 residues. (F) 3D model of PRUNE showing the location and close proximity of the Asp30 and Arg297 amino acid residues.

Mentions: To map the chromosomal location of the causative gene, we performed high density genome-wide SNP mapping assuming that a founder mutation was responsible for the disease in Families A, B and D. This identified a single notable homozygous region of 10.1 Mb of chromosome 1q21.3 in Family A demarcated by rs12033302 and rs11264516, considered likely to correspond to the disease locus. Multipoint linkage analysis was performed on Family A (Sobel et al., 2001), under a model of autosomal-recessive inheritance with full penetrance, producing a highly significant logarithm of the odds (LOD) score across chromosome 1q21.3 (LODmax = 6.07). This region overlapped one of only two notable regions of homozygosity identified in Family B (102.1 Mb demarcated by rs3855975 and rs2274316), as well as one of the two small regions of homozygosity identified in Family D, which spans 3.7 Mb (demarcated by SNPs rs7513205 and rs11265303; Fig. 1 and Supplementary Fig. 2). To identify the causative mutation, we performed whole exome sequencing of a single affected individual from each of Families A and B. After filtering the identified variants for call quality, potential pathogenicity, population frequency and localization within the candidate interval, we identified only a single likely deleterious variant in Family A, a c.88G > A (p.Asp30Asn) alteration in PRUNE1 (NM_021222.2), as the primary candidate mutation. Additionally, exome sequencing identified a c.160C > A (p.Pro54Thr) PRUNE1 sequence variant in Family B and a c.316G > A (p.Asp106Asn) in Family C. A c.889C > T (p.Arg297Trp) alteration in PRUNE1 was subsequently identified in Family D following dideoxy sequencing of all coding exons of this gene (Fig. 1A–D).Figure 1


PRUNE is crucial for normal brain development and mutated in microcephaly with neurodevelopmental impairment
Family pedigrees, genotype and PRUNE mutation. Mutations in PRUNE1 detected in Omani (A); Iranian (B); Italian (C) and Indian (D) families. (E) Alignment of PRUNE amino acid sequence showing stringent conservation of the Asp30; Pro54; Asp106 and Arg297 residues. (F) 3D model of PRUNE showing the location and close proximity of the Asp30 and Arg297 amino acid residues.
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Related In: Results  -  Collection

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awx014-F1: Family pedigrees, genotype and PRUNE mutation. Mutations in PRUNE1 detected in Omani (A); Iranian (B); Italian (C) and Indian (D) families. (E) Alignment of PRUNE amino acid sequence showing stringent conservation of the Asp30; Pro54; Asp106 and Arg297 residues. (F) 3D model of PRUNE showing the location and close proximity of the Asp30 and Arg297 amino acid residues.
Mentions: To map the chromosomal location of the causative gene, we performed high density genome-wide SNP mapping assuming that a founder mutation was responsible for the disease in Families A, B and D. This identified a single notable homozygous region of 10.1 Mb of chromosome 1q21.3 in Family A demarcated by rs12033302 and rs11264516, considered likely to correspond to the disease locus. Multipoint linkage analysis was performed on Family A (Sobel et al., 2001), under a model of autosomal-recessive inheritance with full penetrance, producing a highly significant logarithm of the odds (LOD) score across chromosome 1q21.3 (LODmax = 6.07). This region overlapped one of only two notable regions of homozygosity identified in Family B (102.1 Mb demarcated by rs3855975 and rs2274316), as well as one of the two small regions of homozygosity identified in Family D, which spans 3.7 Mb (demarcated by SNPs rs7513205 and rs11265303; Fig. 1 and Supplementary Fig. 2). To identify the causative mutation, we performed whole exome sequencing of a single affected individual from each of Families A and B. After filtering the identified variants for call quality, potential pathogenicity, population frequency and localization within the candidate interval, we identified only a single likely deleterious variant in Family A, a c.88G > A (p.Asp30Asn) alteration in PRUNE1 (NM_021222.2), as the primary candidate mutation. Additionally, exome sequencing identified a c.160C > A (p.Pro54Thr) PRUNE1 sequence variant in Family B and a c.316G > A (p.Asp106Asn) in Family C. A c.889C > T (p.Arg297Trp) alteration in PRUNE1 was subsequently identified in Family D following dideoxy sequencing of all coding exons of this gene (Fig. 1A–D).Figure 1

View Article: PubMed Central - PubMed

ABSTRACT

Zollo et al. report that mutations in PRUNE1, a phosphoesterase superfamily molecule, underlie primary microcephaly and profound global developmental delay in four unrelated families from Oman, India, Iran and Italy. The study highlights a potential role for prune during microtubule polymerization, suggesting that prune syndrome may be a tubulinopathy.

No MeSH data available.