A Recurrent Intragenic Deletion Mutation in DSG4 Gene in Three Pakistani Families with Autosomal Recessive Hypotrichosis

Rafiq, Muhammad; Ansar, Muhammad; Mahmood, Saqib; Haque, Sayedul; Faiyaz-Ul-Haque, Muhammad; Leal, Suzanne M.; Ahmad, Wasim

doi:10.1111/j.0022-202x.2004.22715.x

Cited by 42 publications

(38 citation statements)

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“…They found abrupt differentiation in the lanceolate hair of Dsg4-mutant mice. Although some reports have been published about human DSG4 mutations (Kljuic et al, 2003;Meyer et al, 2004;Moss et al, 2004;Rafiq et al, 2004;Bazzi et al, 2005;Messenger et al, 2005;Bazzi et al, 2006;Schaffer et al, 2006;Shimomura et al, 2006;Zlotogorski et al, 2006;Farooq et al, 2011), the pathogenesis is quite unclear. Similar to the mouse model, our TEM examinations revealed abnormal keratinization in the cortex and cuticle of the monilethrix hair.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, DSG4 mutations were found to underlie an autosomal recessive monilethrix (OMIM 607903) (Kljuic et al, 2003). To date, only a few cases with DSG4 mutations have been reported (Kljuic et al, 2003;Meyer et al, 2004;Moss et al, 2004;Rafiq et al, 2004;Schaffer et al, 2006;Shimomura et al, 2006;Zlotogorski et al, 2006;Farooq et al, 2011). Although a previous transmission electron microscopy (TEM) study on hereditary monilethrix suggested that hair shaft thinning was induced by the degeneration of hair cortical matrix cells (Ito et al, 1990), the molecular basis for monilethrix, such as the identification of mutation sites and responsible proteins, was not revealed.…”

Section: Introductionmentioning

confidence: 99%

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An Autosomal Recessive Mutation of DSG4 Causes Monilethrix through the ER Stress Response

Kato

Shimizu

Yokoyama

et al. 2015

Journal of Investigative Dermatology

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Monilethrix is a hair shaft anomaly characterized by beaded hair with periodic changes in hair thickness. Mutations in the desmoglein 4 (DSG4) gene reportedly underlie the autosomal recessive form of the disease. However, the pathogenesis and cellular basis for the DSG4 mutation-induced monilethrix remained largely unknown. We report a Japanese female patient with monilethrix. Observation of her hair shaft by means of transmission electron microscopy showed fewer desmosomes and abnormal keratinization. Genetic analysis revealed a homozygous mutation, c.2119delG (p.Asp707Ilefs*109), in the DSG4 gene, which was predicted to cause a frameshift and premature termination in the intracellular region of the DSG4 protein. The mutation has not been reported previously. In the patient's hair shaft, we detected reduced but partial expression of the mutant DSG4 protein. Cellular analyses demonstrated that the mutant DSG4 lost its affinity to plakoglobin and accumulated in the endoplasmic reticulum (ER). The amounts of mutant DSG4 were increased by proteasome inhibitor treatment, and the expression of an ER chaperone, GRP78/BiP, was elevated in the patient's skin. Collectively, these results suggest that the dysfunctional mutated DSG4, tethered in the ER, undergoes ER-associated degradation, leading to unfolded protein response induction, and thus ER stress may have a role in the pathogenesis of monilethrix.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

An Autosomal Recessive Mutation of DSG4 Causes Monilethrix through the ER Stress Response

Kato

Shimizu

Yokoyama

et al. 2015

Journal of Investigative Dermatology

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“…Desmogleins are expressed in the inner epithelial layers of the hair follicles, where their functions appear to be crucial during differentiation of the hair follicle layers (Kljuic et al 2003). Mutations in one member of the desmoglein family of genes, DSG4, have recently been shown to be responsible for localized autosomal recessive hypotrichosis (LAH, Kljuic et al 2003;Rafiq et al 2004;John et al 2006b). These patients suffer from hypotrichosis limited to the scalp, chest, arms and legs (Kljuic et al 2003;Rafique et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Mapping of a Gene for Alopecia with Mental Retardation Syndrome (APMR3) on Chromosome 18q11.2‐q12.2

Wali

Ali

John

et al. 2007

Annals of Human Genetics

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SummaryAlopecia with mental retardation syndrome (APMR) is a rare autosomal recessive disorder characterized by total or partial absence of hair from the scalp and other parts of the body and associated with mental retardation. Previously, we have reported the mapping of two alopecia and mental retardation genes (APMR1 and APMR2) on human chromosome 3. In the present study, after excluding both of these loci through linkage analysis, a whole genome scan was performed by genotyping 396 polymorphic microsatellite markers located on 22 autosomes and the X and Y chromosomes. A disease locus was mapped to a 10.9 cM region, flanked by markers D18S866 and D18S811, on chromosome 18q11.2-q12.2. A maximum two-point LOD score of 3.03 at θ = 0.0 was obtained with marker D18S1102. Multipoint linkage analysis resulted in maximum LOD scores of 4.03 with several markers in the candidate region. According to the Rutgers combined linkage-physical map of the human genome (build 36) this region covers 12.17 Mb. DNA sequence analysis of nine candidate genes including DSC3, DSC1, DSG1, DSG4, DSG3, ZNF397, ZNF271, ZNF24 and ZNF396 did not reveal any sequence variants in the affected individuals of the family presented here.

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“…This included congenital atrichia (MIM 203655) at 8p21 Nothen et al 1998), localized hereditary hypotrichosis (LAH, MIM 607903) at 18q12.1 (Kljuic et al 2003;Rafique et al 2003), autosomal recessive hereditary hypotrichosis (LAH2, MIM 609167) at 3q27.2 (Aslam et al 2004), LAH3 (MIM 611452) at 13q14.11-q21.32 (Wali et al 2007a) and hereditary hypotrichosis with skin vesicles (MIM 613102) at 18q21.1 ). All these five conditions congenital atrichia, LAH1, LAH2, LAH3 and hereditary hypotrichosis with skin vesicles have been reported to result from mutations in hairless (HR, MIM 225060) Cichon et al 1998), desmoglein 4 (DSG4, MIM 607892) (Kljuic et al 2003;Rafiq et al 2004), lipase-H (LIPH, MIM 607365) (Kazantseva et al 2006;Ali et al 2007), G-protein coupledreceptor (P2RY5, MIM 609239) (Pasternack et al 2008;Shimomura et al 2008;Azeem et al 2008;Tariq et al 2009) and desmocollin-3 (DSC3, MIM 600271) ) genes, respectively. An autosomal dominant form of isolated hypotrichosis simplex of the scalp has been shown to result from mutations in corneodesmosin gene (CDSN, MIM 602593) (Levy-Nissenbau et al 2003).…”

Section: Introductionmentioning

confidence: 99%

Mapping of a novel autosomal recessive hypotrichosis locus on chromosome 10q11.23–22.3

et al. 2010

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Autosomal recessive hypotrichosis is a rare form of human genetic disorder characterized by sparse to absent hair on scalp and rest of the body of affected individuals. Over the past few years at least five autosomal recessive forms of hypotrichosis loci have been mapped on different human chromosomes. In the present study, we report localization of another novel autosomal recessive hypotrichosis locus on human chromosome 10q11.23-22.3 in a four generation consanguineous Pakistani family. All the four patients in the family showed typical features of hereditary hypotrichosis including sparse hair on the scalp and rest of the body. Human genome scan using highly polymorphic microsatellite markers mapped the disease locus to a large region on chromosome 10. This novel locus maps to 29.81 cM (28.5 Mb) region, flanked by markers D10S538 and D10S2327 on chromosome 10q11.23-22.3. A maximum multipoint LOD score of 3.26 was obtained with several markers in this region. DNA sequence analysis of exons and splice-junction sites of four putative candidate genes (P4HA1, ZNF365, ZMYND17, MYST4), located in the linkage interval, were sequenced but were negative for functional sequence variants.

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A Recurrent Intragenic Deletion Mutation in DSG4 Gene in Three Pakistani Families with Autosomal Recessive Hypotrichosis

Cited by 42 publications

References 15 publications

An Autosomal Recessive Mutation of DSG4 Causes Monilethrix through the ER Stress Response

An Autosomal Recessive Mutation of DSG4 Causes Monilethrix through the ER Stress Response

Mapping of a Gene for Alopecia with Mental Retardation Syndrome (APMR3) on Chromosome 18q11.2‐q12.2

Mapping of a novel autosomal recessive hypotrichosis locus on chromosome 10q11.23–22.3

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