Two Genes Are Responsible for Griscelli Syndrome at the Same 15q21 Locus

doi:10.1006/geno.1999.6081

Genomics

Volume 63, Issue 3, 1 February 2000, Pages 299-306

https://doi.org/10.1006/geno.1999.6081 Get rights and content

Abstract

Griscelli syndrome is a rare autosomal recessive disease characterized by pigment dilution, variable cellular immunodeficiency, and an acute phase of uncontrolled T lymphocyte and macrophage activation. We previously mapped the disease locus to 15q21 and showed that a MyoVa gene (HGMW-approved symbol MYO5A) defect leads to Griscelli syndrome. We report a second MyoVa mutation in a new patient, confirming this first finding. However, in four other Griscelli syndrome patients analyzed, the MYOVA protein is expressed, and no mutation can be detected in the MyoVa gene coding sequence, even in the alternatively spliced region for which exon–intron boundaries were characterized. Linkage analysis performed in 15 Griscelli families thus far studied confirms the first localization. However, fine haplotype analysis in three families strongly suggests the existence of a second gene at the same locus for Griscelli syndrome less than 7.3 cM distant from the MyoVa gene.

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Genome-wide association studies for tick resistance in Bos taurus × Bos indicus crossbred cattle: A deeper look into this intricate mechanism
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The MYO5A gene (window 3, Table 1) showed connections to a set of TF (TALL3::TCF3, NFIL3, EGR1, and PAX5). This gene encodes the myosin Va protein found in melanocytes and, along with other proteins, assists in the melanosomes transport, which are structures that produce the melanin pigment responsible for pigmentation of skin, hair, and eyes (Pastural et al., 2000; Hume and Seabra, 2011). Melanocytes play an important role in the innate immune response, controlling microbial infection and inflammation, as these cells contribute to phagocytosis of invading pathogens.
Rhipicephalus (Boophilus) microplus is the main cattle ectoparasite in tropical areas. Gir × Holstein crossbred cows are well adapted to different production systems in Brazil. In this context, we performed genome-wide association study (GWAS) and post-GWAS analyses for R. microplus resistance in an experimental Gir × Holstein F₂ population. Single nucleotide polymorphisms (SNP) identified in GWAS were used to build gene networks and to investigate the breed of origin for its alleles. Tick artificial infestations were performed during the dry and rainy seasons. Illumina BovineSNP50 BeadChip (Illumina Inc., San Diego, CA) and single-step BLUP procedure was used for GWAS. Post-GWAS analyses were performed by gene ontology terms enrichment and gene transcription factors networks, generated from enriched transcription factors, identified from the promoter sequences of selected gene sets. The genetic origin of marker alleles in the F₂ population was assigned using the breed of origin of alleles approach. Heritability estimates for tick counts were 0.40 ± 0.11 in the rainy season and 0.54 ± 0.11 in the dry season. The top ten 0.5-Mbp windows with the highest percentage of genetic variance explained by SNP markers were found in chromosomes 10 and 23 for both the dry and rainy seasons. Gene network analyses allowed the identification of genes involved with biological processes relevant to immune system functions (TREM1, TREM2, and CD83). Gene-transcription factors network allowed the identification of genes involved with immune functions (MYO5A, TREML1, and PRSS16). In resistant animals, the average proportion of animals showing significant SNPs with paternal and maternal alleles originated from Gir breed was 44.8% whereas the proportion of animals with both paternal and maternal alleles originated from Holstein breed was 11.3%. Susceptible animals showing both paternal and maternal alleles originated from Holstein breed represented 44.6% on average, whereas both paternal and maternal alleles originated from Gir breed animals represented 9.3%. This study allowed us to identify candidate genes for tick resistance in Gir × Holstein crossbreds in both rainy and dry seasons. According to the origin of alleles analysis, we found that most animals classified as resistant showed 2 alleles from Gir breed, while the susceptible ones showed alleles from Holstein. Based on these results, the identified genes may be thoroughly investigated in additional experiments aiming to validate their effects on tick resistance phenotype in cattle.
Dendritic spine actin cytoskeleton in autism spectrum disorder
2018, Progress in Neuro-Psychopharmacology and Biological Psychiatry
Citation Excerpt :
Myosin Va plays a critical role in spine and synapse development by trafficking the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors into dendritic spines (Yoshii et al., 2013). Mutations in MYO5A cause severe neurological defects, including intellectual disability and seizures (Pastural et al., 2000; Thomas et al., 2009). Myosin XVI (MYO16) is an unconventional actin-based molecular motor with ATPase activity (Fig. 3).
Dendritic spines are small actin-rich protrusions from neuronal dendrites that form the postsynaptic part of most excitatory synapses. Changes in the shape and size of dendritic spines correlate with the functional changes in excitatory synapses and are heavily dependent on the remodeling of the underlying actin cytoskeleton. Recent evidence implicates synapses at dendritic spines as important substrates of pathogenesis in neuropsychiatric disorders, including autism spectrum disorder (ASD). Although synaptic perturbations are not the only alterations relevant for these diseases, understanding the molecular underpinnings of the spine and synapse pathology may provide insight into their etiologies and could reveal new drug targets. In this review, we will discuss recent findings of defective actin regulation in dendritic spines associated with ASD.
Oligomerization of Rab/effector complexes in the regulation of vesicle trafficking
2013, Progress in Molecular Biology and Translational Science
Citation Excerpt :
Patients with this rare autosomal disorder exhibit dilution of skin and hair pigment from accumulation of pigment-bearing melanosomes in melanocytes and neurological disorders.169 Many patients also develop virus-associated hemophagocytic syndrome (HS) that involves uncontrolled T-cell and macrophage activation, which leads to death in the absence of a bone marrow transplant.169,170 Initially, the genetic mutation was mapped to the gene corresponding to myosin Va (MYOVA)170 and an associated gene, RAB27A.140
Rabs comprise the largest member of the Ras superfamily of small GTPases with over 60 proteins in mammals and 11 proteins in yeast. Like all small GTPases, Rabs oscillate between an inactive GDP-bound conformation and an active GTP-bound state that is tethered to lipid membranes via a C-terminal prenylation site on conserved cysteine residues. In their active state, Rabs regulate various aspects of membrane trafficking, including vesicle formation, transport, docking, and fusion. The critical element of biological activity is the recruitment of cytosolic effector proteins to specific endomembranes by active Rabs. The importance of Rabs in cellular processes is apparent from their links to genetic disorders, immunodeficiency, cancer, and pathogen invasion. During the last decade, numerous structures of complexes have shed light on the molecular basis for Rab/effector specificity and their topological organization on subcellular membranes. Here, I review the known structures of Rab/effector complexes and their modes of oligomerization. This is followed by a brief discussion on the thermodynamics of effector recruitment, which has not been documented sufficiently in previous reviews. A summary of diseases associated with Rab/effector trafficking pathways concludes this chapter.
Disorders of Leukocyte Function
2013, Emery and Rimoin's Principles and Practice of Medical Genetics
Abnormalities of Pigmentation
2013, Emery and Rimoin's Principles and Practice of Medical Genetics
Rab27a in pancreatic beta-cells, a busy protein in membrane trafficking
2011, Progress in Biophysics and Molecular Biology
Citation Excerpt :
Mutations in the Rab27a gene cause a human genetic disease, Gricelli syndrome. Patients suffering from Gricelli syndrome exhibit immunodeficiency and pigment dilution in hair (Menasche et al., 2000; Pastural et al., 2000). Identification and the characterization of its effectors revealed the roles of Rab27a in Rab27a-expressing cells such as T-lymphocytes and melanocytes.
The small GTPases have the ‘active’ GTP-bound and ‘inactive’ GDP-bound states, and thereby act as a molecular switch in cells. Rab27a is a member of this family and exists in T-lymphocytes, melanocytes and pancreatic beta-cells. Rab27a regulates secretion of cytolytic granules from cytotoxic T-lymphocytes and intracellular transport of melanosomes in melanocytes. In pancreatic beta-cells, Rab27a controls pre-exocytotic stages of insulin secretion. A few GTP-dependent Rab27a effectors are known to mediate these cellular functions. We recently found that Rab27a also possesses the GDP-dependent effector coronin 3. Coronin 3 regulates endocytosis in pancreatic beta-cells through its interaction with GDP-Rab27a. These results imply that GTP- and GDP-Rab27a actively regulate distinct stages in the insulin secretory pathway. In this review, we provide an overview of the roles of both GTP- and GDP-Rab27a in pancreatic beta-cells.

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¹: To whom correspondence should be addressed. Telephone: 33 1 44 49 50 80. Fax: 33 1 42 73 06 40. E-mail: [email protected].

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Genomics

Abstract

References (30)

Cloning and mRNA expression of human unconventional myosin-IC: A homologue of amoeboid myosins-I with a single IQ motif and an SH3 domain

J. Mol. Biol.

Brain myosin-V is a two-headed unconventional myosin with motor activity

Cell

A syndrome associating partial albinism and immunodeficiency

Am. J. Med.

Mapping of unconventional myosins in mouse and human

Genomics

Partial albinism with immunodeficiency (Griscelli syndrome)

J. Pediatr.

Human myosin V gene produces different transcripts in a cell type-specific manner

Biochem. Biophys. Res. Commun.

The dilute-lethal (dl) gene attacks a Ca²⁺ store in the dendritic spine of Purkinje cells in mice

Neurosci. Lett.

Construction of yeast artificial chromosome library containing seven haploid human genome equivalents

Proc. Natl. Acad. Sci. USA

Genetic and physical mapping of the Chédiak–Higashi syndrome on chromosome 1q42–43

Am. J. Hum. Genet.

Mutations affecting pigmentation in man. 1. Neuroectodermal melanolysosomal disease

Am. J. Med. Genet.

Methodology in Medical Genetics

Griscelli disease with cerebral involvement

Eur. J. Pediatr.

Molecular genetic dissection of mouse unconventional myosin-VA: Head region mutations

Genetics

Molecular genetic dissection of mouse unconventional myosin-VA: Tail region mutations

Genetics

Cited by (94)

Genome-wide association studies for tick resistance in Bos taurus × Bos indicus crossbred cattle: A deeper look into this intricate mechanism

Dendritic spine actin cytoskeleton in autism spectrum disorder

Oligomerization of Rab/effector complexes in the regulation of vesicle trafficking

Disorders of Leukocyte Function

Abnormalities of Pigmentation

Rab27a in pancreatic beta-cells, a busy protein in membrane trafficking

Regular ArticleTwo Genes Are Responsible for Griscelli Syndrome at the Same 15q21 Locus

Abstract

J. Mol. Biol.

Cell

Am. J. Med.

Genomics

J. Pediatr.

Biochem. Biophys. Res. Commun.

Neurosci. Lett.

Construction of yeast artificial chromosome library containing seven haploid human genome equivalents

Proc. Natl. Acad. Sci. USA

Genetic and physical mapping of the Chédiak–Higashi syndrome on chromosome 1q42–43

Am. J. Hum. Genet.

Mutations affecting pigmentation in man. 1. Neuroectodermal melanolysosomal disease

Am. J. Med. Genet.

Methodology in Medical Genetics

Griscelli disease with cerebral involvement

Eur. J. Pediatr.

Molecular genetic dissection of mouse unconventional myosin-VA: Head region mutations

Genetics

Molecular genetic dissection of mouse unconventional myosin-VA: Tail region mutations

Genetics

Regular Article
Two Genes Are Responsible for Griscelli Syndrome at the Same 15q21 Locus