Clin Genet 2014 Printed in Singapore. All rights reserved
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd CLINICAL GENETICS doi: 10.1111/cge.12531
Review
Genetics of human isolated hereditary hair loss disorders Basit S., Khan S., Ahmad W. Genetics of human isolated hereditary hair loss disorders. Clin Genet 2014. © John Wiley & Sons A/S. Published by John Wiley & Sons Ltd, 2014 Hereditary hair loss in human is a group of clinically and genetically heterogeneous disorders. It is characterized by sparse to complete absence of hair on the scalp and other parts of the body. In few cases tightly curled twisted wooly hair (WH) on the scalp has been reported as well. The hair loss disorders, including both syndromic and non-syndromic (isolated) forms, segregate either in autosomal dominant or autosomal recessive pattern. To date, seven autosomal dominant and equal numbers of autosomal recessive isolated forms of hair loss disorders have been characterized. Genes responsible for causing most of these disorders have been identified. In this review, we have provided an update on clinical and genetic aspects of isolated hereditary hair loss disorders manifesting with hypotrichosis and/or WHs. Because most of the recessive genes have been mapped using consanguineous families of Pakistani origin, therefore emphasis is given to mutations identified in these families. OMIM nomenclature has been followed to indicate different forms of hair loss disorders. Conflict of interest
The authors declare no conflicts of interest.
S. Basita , S. Khanb and W. Ahmadc a Center for Genetics and Inherited Diseases, Taibah University, Almadinah Almunawwarah, Saudi Arabia , b Department of Biotechnology and Genetic Engineering, Kohat University of Science and Technology, Khyber Pakhtunkhwa, Pakistan , and c Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
Key words: disease-causing mutations – heterogeneity – hereditary hair loss – isolated forms Corresponding author: Sulman Basit, PhD, Center for Genetics and Inherited Diseases, Taibah University, Almadinah Almunawwarah, Kingdom of Saudi Arabia. Tel.: +966 535370209; fax: 925192519205753 e-mail:
[email protected] Received 24 August 2014, revised and accepted for publication 23 October 2014
Hereditary hair loss in human is a heterogeneous group of disorders characterized by sparse to complete absence of hair on the scalp and other parts of the body. Hereditary hair growth abnormalities manifest as either hypertrichosis (excess hair) or hypotrichosis (lack/sparse hair). Hypotrichosis can grossly be characterized into two major groups depending upon the absence (isolated) or presence (syndromic) of non-dermatological features such as retinal degeneration, intellectual disability, and hearing impairment. At least seven autosomal dominant and equal numbers of autosomal recessive forms of isolated hair loss disorders have been mapped on different human chromosomes and, except in three cases, the corresponding genes have been discovered. The autosomal dominant forms of hair loss disorders have been shown to result from mutations in the genes adenomatosis polyposis downregulated 1 (APCDD1, MIM 607479, HYPT1) (1),
corneodesmosin (CDSN, MIM 602593, HYPT2) (2), keratin-74 (KRT74, MIM 608248, HYPT3) (3), in the inhibitory upstream open reading frame (U2HR) of the hairless (HR) gene (U2HR, MIM 146550, HYPT4) (4, 5), epidermal growth factor receptor pathway substrate 8-like 3 gene (EPS8L3, MIM 614989, HYPT5) (6), small nuclear ribonucleoprotein polypeptide E (SNRPE, MIM 128260, HYPT11) gene (7) and ribosomal protein L21 (RPL21, MIM 603636, HYPT12) gene (8). The autosomal recessive forms of hair loss disorders have been shown to result from mutations in the genes including hairless (HR, MIM 225060) (9, 10), desmoglein-4 (DSG4, MIM 607892, HYPT6) (11), lipase-H (LIPH, MIM 607365, HYPT7) (12, 13), lysophosphatidic acid receptor 6 (LPAR6/P2RY5, MIM 609239, HYPT8) (14–17) and desmocollin-3 (DSC3, MIM 600271) (18). The genes for two other autosomal recessive forms of
1
Basit et al. hair loss disorders (HYPT9-10) have not been identified yet (19–21). Autosomal dominant forms of hereditary hair loss disorders Hereditary hypotrichosis simplex type 1 (HHS1/HYPT1)
Hereditary hypotrichosis simplex (HHS) of scalp is a descriptive term for the clinical expression of a variety of phenomena related to diffuse thinning of the scalp hair without any gross abnormality of the hair shaft morphology or associated anomalies. Affected members with this condition present thin, sparse and short scalp and body hair. The hair growth is particularly sparse at the top of the head, somewhat denser hair growth is observed at the temples. A thin and sparse re-growth of the scalp hair is observed after cutting. Eyebrows, eyelashes, and beard hair are normal (Table 1). Baumer et al. (22) mapped the gene for HYPT1 phenotype on chromosome 18p11.32-p11.23. Later, Shimomura et al. (1) in two Pakistani families mapped the HHS1 phenotype to the same chromosomal region. Molecular analysis of all three families including two Pakistani and an Italian revealed adenomatosis polyposis coli downregulated 1 (APCDD1, MIM 607479) gene responsible for causing this phenotype (1). To date, only a single missense mutation (p.Leu9Arg) has been reported in the APCDD1 gene in four families originating from different ethnic groups (1, 23). The APCDD1 gene comprises of five exons and spans 40 kb region on chromosome 18p11.32-p11.23 (24). APCDD1 is a membrane tethered protein that abundantly expressed in dermal papilla and hair shaft of human hair follicle (HF). Functional studies revealed that APCCD1 functions upstream of β-catenin and shows inhibitory effects on Wnt signaling, and it was hypothesized that it may act as potential regulator of diverse biological processes by impinging Wnt signaling (1). Hypotrichosis simplex of scalp type 2 (HSS2/HYPT2)
Clinical features observed in affected members with HSS1 have been reported in another dominant form of hypotrichosis simplex of the scalp (HSS2). The condition manifests with sparse hair appearing at birth or in early childhood and progressing into adulthood. Eyebrows, eyelashes, beard and other body hair are normal (Table 1). Betz et al. (25) mapped a gene for this disorder on chromosome 6p21.3. Later, three other groups identified disease-causing nonsense mutations (p.Gln215*, p.Gln200*, and p.Tyr239*) in the gene Corneodesmosin (CDSN, MIM 602593) in families originating from Israel, Spain, Denmark and Mexico (2, 26, 27) (Table S1, Supporting information). The gene CDSN encodes 529 amino acids glycoprotein. Corneodesmosin is a late differentiation epidermal protein, and it act as a keratinocyte adhesion molecule. It expresses in the epidermis and inner root sheath (IRS) of HF where it is involved in the cell cohesion (2). Later, it has been reported that CDSN has essential role
2
throughout life in skin barrier preservation by maintaining desmosomal integrity, and hence it seems to maintain hair architecture (28). Hereditary hypotrichosis 3 (HYPT3) and wooly hairs
Hereditary hypotrichosis 3 (HYPT3) and presence of wooly hair (WH) on the scalp are another rare hair loss disorder segregating in autosomal dominant manner. Patients with HYPT3 show coarse, lusterless, dry and tightly curled hair leading to a diffuse WH phenotype. Under light microscope, plucked hairs from affected individuals showed anomalies including dystrophic anagen hair, twisting, knot formation, and tapered distal ends (Fig. 1a). The gene for this phenotype was mapped on chromosome 12q12-q14.1 (3). Sequence analysis of KRT74 gene led to the identification of two missense (p.Asn148Lys, p.Asp482Asn) and one splice site (c.IVS8-1G>A) mutations in three Pakistani families (3, 29) (Table S1). In one of the two families reported by Wasif et al. (29), only features of hypotrichosis were observed in the affected members. The KRT74 gene is composed of nine exons encoding 529 amino acids K74 protein. Like other keratins, K74 is composed of N-terminal head domain, the central helical rod domain and C-terminal tail domain. Shimomura et al. (3) have reported that K74 specifically expresses in Huxley layer, which plays an important role in maintaining the structure of HF. Hypotrichosis 4 (HYPT4)/Marie Unna hereditary hypotrichosis 1
Marie Unna hereditary hypotrichosis (MUHH1, MIM 146550), an autosomal dominant genetic hair loss disorder, is characterized by sparse or absent hair at birth, development of coarse hair in early childhood with progressive hair loss leading to varying degrees of alopecia in adults (Table 1). At least five different groups mapped the gene for MUHH to human chromosome 8p21 (30–34). After failing to find disease-causing variants in the human hairless (HR) gene, four upstream open reading frames (ORFs) in the 5′ untranslated region (UTR) of the HR designated as U1HR, U2HR, U3HR and U4HR were screened in several families. Sixteen distinct heterozygous mutations in the U2HR of the HR gene in these families segregating HYPT4 from different ancestral groups have been reported to date (4, 5, 35–39) (Table S1). U2HR, specifies a highly conserved peptide of 34 amino acids, is an inhibitory upstream ORF in the 5′ UTR of the HR gene. Wen et al. (4) and Kim et al. (40) have shown that mutation in U2HR results in increase in expression of the HR resulting in causing disruption in HF morphogenesis and cycling. Hypotrichosis 5 (HYPT5)/MUHH2
Hypotrichosis 5 (HYPT5, MIM 612841) is another form of MUHH2. Features of the patients with HYPT5 are similar to those observed in patients with MUHH1
Genetics of hereditary hair loss disorders
Fig. 1. Clinical presentation of hereditary hair loss disorders. Phenotypic appearance of an individual affected with HYPT 3 (a), APL (b), HYPT 6 (c), HYPT 7 (d), HYPT 8 (e), HYPT9 (f), HYPT10 (g), and Digenic autosomal recessive hypotrichosis (h).
(Table 1). In a Chinese family, Yan et al. (41) described features including absent hair on scalp at birth, and then development of thin wire like irregular hair in childhood, thin eyebrows and eyelashes, absent axillary and pubic hair. Exome sequencing led to the identification of a missense mutation (p.Ala8Thr) in the gene EPS8L3 causing MUHH2 (6). This is the only mutation reported in the gene EPS8L3 underlying HYPT5. Hereditary hypotrichosis simplex 3 (HHS3/HYPT11)
Affected individuals in families segregating autosomal dominant form of hypotrichosis (HHS3/HYPT11) show highly variable degree of hair disorders since birth, ranging from slight thinning of scalp and axillary hair to complete loss of scalp and body hair. Most of the affected individuals present with scanty or no eyebrows. Pubic
hair remains mainly unaffected (7, 42) (Table 1). Linkage analysis followed by Sanger sequencing identified an SNRPE, located on chromosome 1q31.3-1q41, involved in causing HYPT11 in three families collected from Spain, United Kingdom and Tunisia (7). To date, two mutations (p.Met1? and p.Gly45Ser) have been reported in the gene SNRPE (Table S1). The gene SNRPE consists of five coding exons which encode 92 amino acid protein SNRPE. SNRPE protein constitutes a core component of U-rich small nuclear ribonucleoproteins (U snRNPs). These RNA-protein particles are part of the spliceosome, which catalyzes the excision of introns from primary gene transcripts during the splicing process. SNRPE is expressed ubiquitously including skin and HF cells (7).
3
4 U2HR
EPS8L3
DSG4
6p21.3
12q13
8p21.2
1p13.3
18q12
Hypotrichosis simplex of scalp type 2 (HSS2/HYPT2)
Dominant hereditary hypotrichosis 3 and WHs (HYPT3)
Marie Unna hereditary hypotrichosis 1/hypotrichosis 4 (MUHH1/HYPT4) Marie Unna Hereditary hypotrichosis 2/hypotrichosis 5 (MUHH1/HYPT5) Localized autosomal recessive hypotrichosis 1/hypotrichosis 6 (LAH1/HYPT6)
Yet to be discover Yet to be discover SNRPE
10q11.23-q22.3
7p22.3-p21.3
1q32.1
Localized autosomal recessive hypotrichosis 4/hypotrichosis 9 (LAH4/HYPT9) Localized autosomal recessive hypotrichosis 5/hypotrichosis 10 (LAH5/HYPT10) Hypotrichosis simplex of scalp type 3 (HSS3/HYPT11)
LPAR6
13q14
Localized autosomal recessive hypotrichosis 3/hypotrichosis 8 (LAH3/HYPT8)
LIPH
3q27.2
Localized autosomal recessive hypotrichosis 2/hypotrichosis 7 (LAH2/HYPT7)
KRT74
CDSN
APCDD1
18p11.22
Hypotrichosis simplex of scalp type 1 (HSS1/HYPT1)
Gene
Genetic locus
Disease
Table 1. Phenotypic variability in isolated hereditary hair loss disorders
Sparse, thin and slightly brown hair on scalp, arms and legs. Normal eyebrows and eyelashes Complete absence of hair at birth. Eyebrows, eyelashes and body hairs are sparse. Papules on scalp Thin scalp and axillary hair to complete absence of scalp and body hair , sparse to absent eyebrows, normal pubic hair
Sparse to absent scalp hair at birth. Wiry, irregular hair in childhood. Thin eyebrows, eyelashes Sparse scalp hairs, absence of eyebrows and eyelashes, normal axillary and pubic hairs, follicular papules on scalp Sparse, thin, fragile and short scalp hair. Wooly, tightly curled, light colored scalp hair. Normal to sparse eyebrows, eyelashes, axillary and body hair Tightly curled, wooly, fragile and slow growing hair, normal to sparse eyebrows and eyelashes, popular lesions on the occipital region
Sparse, short and thin hair on scalp and body. Eyebrows, eyelashes and beard hair are normal Normal hair at birth, scalp hair growth retardation with diffuse hair loss, sparse hair on scalp, body. Eyebrows, eyelashes and beard hair are normal Sparse scalp hair. Coarse, lusterless, tightly curled WH. Eyebrows, eyelashes, and beard hair are normal Slow growing sparse and fragile hair
Phenotype
No abnormalities of HS
NA
NA
Absent root sheath component in the bulb region
Coarse, short, brittle and fragile HS, trichoschisis, pili torti, uneven HS diameter, tapered end Twisted HS with tapered distal ends
NA
Dystrophic anagen hair. HS twisted with tapered distal ends NA
No HS abnormality
No HS abnormality
HS abnormalities
Vellus type of HF
Markedly reduce number of HF,
Small sized HF with dilation of lower infundibula, comedo-like HF with hyperkeratinized infundibula NA
Comedo-like HF with hyperkeratinization
NA
Markedly reduced mature HFs
NA
NA
NA
NA
HF abnormalities
Basit et al.
Genetics of hereditary hair loss disorders
NA NA
Affected individuals segregates HYPT12 phenotype in an autosomal dominant manner characterize with normal scalp hair density at birth. Hair loss began at approximately 2–6 months of age and gradually progressed with age to complete loss of scalp hair. The remaining hairs length could reach the length of normal hair but grew slowly, and remain thin, sparse, dry, and fragile. Eyebrows, eyelashes, body hair, and axillary and pubic hairs are also sparse to completely absent. Beard hairs, however, are not affected (Table 1). HYPT12 has been mapped to chromosome 13q12.12-12.3 (43). Exome sequencing identified mutation in the gene ribosomal protein L12 (RPL21) in three Chinese families. The RPL21 gene encodes a ribosomal protein of 160 amino acids residues that is a component of the 60S subunit. To date, only one heterozygous mutation (p.Arg32Gln) has been reported in the gene RPL21 (8) as a cause of HYPT12. Autosomal recessive forms of hereditary hair loss disorders Atrichia with papular lesions
HF, hair follicle; NA, not applicable; WH, wooly hair.
16q22.1 and 12q21.2-q22 Digenic autosomal recessive hypotrichosis
CDH3 and an unknown gene
Slight follicular plugging NA 18q12.1 Hypotrichosis with recurrent skin vesicles
DSC3
HF significantly decreased in number and size No HS anomaly
Normal hair at birth, hair loss began at 2–6 months of age, absent to sparse scalp hair, eyebrows, eyelashes, body hair, and axillary and pubic hairs Sparse scalp hair, absence of eyebrows, eyelashes, axillary and body hair, skin vesicles of T, p.Pro267Arg; p.Arg289*, IVS216+1G>T; c.763delT, p.Pro267Arg; c.763delT, c.624delG; p.W823*, p.Ser192Pro; and c.2039insT) responsible for causing monilethrix phenotype (63, 67, 68) have been reported as well (Table S1). The DSG4 gene consists of 16 exons and encodes a member of desmosomal cadherin superfamily. It is expressed in the inner epithelial layers of the HF specifically in the cortex region of the hair shaft, lower hair cuticle and upper IRS in human (11, 69) where it constitutes a part of desmosomes. Desmosomes has an important role in cell-to-cell adhesion and is crucial for proper HF development and differentiation (63, 68). The extracellular domains of the desmoglein and desmocollins mediate adhesion through homo/heterophillic interactions (70) while their cytoplasmic tails associate with desmosomal protein plaques.
HYPT7 is characterized by sparse WH (71, 72) to normal fine thin hair growth on the scalp at birth (12, 13, 73–75). Affected members gradually deprive of their hair, which appear thin, fragile and short at adult age (12, 72). WH on the entire scalp is tightly curled, light colored, with hair density from normal to less dense (71, 72). Tightly curled hairs grow slowly and stop growing after a few inches (76). Normal to sparse eyebrows, eyelashes, axillary hair and body hair were reported in the affected members; however, male members have developed normal beard hair (13, 71, 73, 74) (Fig. 1d). Light microscopy of plucked hairs reveal twisting of hair shaft with tapered distal ends (71, 72). Histopathological analysis revealed that normal HF structures are replaced by comedo-like remnants which undergo hyperkeratinization (Table 1). Aslam et al. (73) mapped HYPT7 to chromosome 3q27.3 in a consanguineous family. Further genetic studies on families segregating hereditary hypotrichosis in two ethnic groups, the Chuvash and Mari, in Russia, identified LIPH as a causative gene in HYPT7 locus (12). These authors detected a common founder deletion mutation eliminating exon 4 and its flanking intronic sequences in 3,50,000 individuals from the two ethnic groups. So far, 14 mutations in the LIPH gene have been reported in families segregating HYPT7 (12, 13, 71, 72, 74, 75, 77–83) (Table S1). Mutations in LIPH gene have been reported in 33 families of Pakistani origin. Two deletion mutations c.659_660delTA and Ex7_8del have been detected in 12 and 8 families, respectively. The LIPH gene, which encodes membrane-associated phosphatidic acid-preferring phospholipaseA1α (PA-PLA1α), contains 10 exons and is expressed in several tissues including testis, ovary, pancreas, kidney, lung, spleen, brain, heart and HF. PA-PLA1α, a 55 kDa protein, has been shown to promote conversion of phosphatidic acid to acyl-lysophosphatidic acid (LPA) (84), a ligand for the P2Y5,the lysophosphatidic acid receptor 6 encoded by LPAR6, which has also been implicated in hypotrichosis (HYPT8). Expression of P2Y5 partially overlaps with that of PA-PLA1α in HFs (14).
6
Localized autosomal recessive hypotrichosis (LAH3; HYPT8)
Patients with third localized autosomal recessive form of hypotrichosis, LAH3, exhibit normal to tightly curled wooly, fragile and slow growing hairs (14, 16, 17, 85). Hairs regrow sparsely after ritual shaving that shed progressively and gradually replaces with thin, curly light colored hair (16, 86). Eyelashes and eyebrows, and axillary and pubic hairs are normal to sparse (14, 16, 86). Papular lesions are either absent (87) or present where they are localized only to occipital region (14) (Fig. 1e). Hair shaft examination by light microscopy revealed no abnormalities (15) to dystrophic features without root sheath components in the bulb portion and the distal portion of the hair shaft were frequently broken (14).
Genetics of hereditary hair loss disorders A scalp skin biopsy from an affected individual showed reduced number of small sized HFs with dilation of lower follicle infundibula (85–87) (Table 1). Genome wide homozygosity mapping identified a chromosomal region 13q14.11-q21.32 for HYPT8 (88), and subsequently two groups independently showed that mutations in lysophosphatidic acid receptor 6 encoding gene (LPAR6/P2RY5) located at HYPT8 candidate region are responsible for developing hypotrichosis and WH phenotype (14, 15). To date, 23 mutations have been reported in families segregating HYPT8 phenotype (Table S1). Eleven of these mutations have been detected in 41 consanguineous families of Pakistani origin (16, 17, 83). The missense mutation (p.Gly146Arg) is the most prevalent mutation found in 12 families segregating HYPT8. The LPAR6 gene is embedded within intron of RB1 gene and consists of a single exon with a putative ORF of 344 amino acids. The P2Y5 protein, encoded by the LPAR6 gene, resembles P2Y family of purinergic G-protein coupled receptors GPCRs on the basis of sequence homology and contains seven predicted hydrophobic transmembrane regions (89). Expression of P2Y5 has been detected in the Henle’s and Huxley’s layers of the IRSs of HF and suprabasal layer of epidermis where its expression increases with differentiation (14). Autosomal recessive hypotrichosis (HYPT9)
Recently, Naz et al. (19) mapped another autosomal form of recessive hypotrichosis (HYPT9) on chromosome 10q11.23-22.3 in a consanguineous Pakistani family. Affected members in the family presented features similar to those observed in patients in the families segregating other autosomal recessive forms of hypotrichosis (Fig. 1f) (Table 1). Causative gene for HYPT9 has not been identified yet. Autosomal recessive hypotrichosis (HYPT10)
HYPT10 was mapped in large Pakistani family in 6.59 Mb region on chromosome 7p21.3-p22.3 flanked by microsatellite marker D7S1532 and D7S3047 (20). Individuals affected with HYPT10 were born with complete absence of scalp hairs. Eyebrows, eyelashes and body hairs were sparse. Beard and mustaches were sparse to normal and thick. Affected individuals have papules restricted to scalp only (Fig. 1g). A scalp skin biopsy showed markedly reduced number of HFs (Table 1). Causative gene at HYPT10 has not been identified yet. Hypotrichosis with recurrent skin vesicle
This unique type of hypotrichosis was described in a consanguineous family of Afghan origin in which affected members reported to have hairs on the scalp at birth that shed in few weeks but grew back after ritual shaving (18). The hairs were fragile, fell at 2–3 months of age and later only sparse hairs left on the scalp. Affected individuals were nearly devoid of normal eyelashes, eyebrows, axillary hair and body hair. Vesicles T in a Chinese patient with Marie Unna hereditary hypotrichosis. Eur J Dermatol 2012: 22: 34–35. 36. Ramot Y, Horev L, Smolovich I, Molho-Pessach V, Zlotogorski A. Marie Unna hereditary hypotrichosis caused by a novel mutation in the human hairless transcript. Exp Dermatol 2010: 19: e320–e322.
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