Whole‐Exome Sequencing Identifies a Variant in TMEM132E Causing Autosomal‐Recessive Nonsyndromic Hearing Loss DFNB99

Autosomal‐recessive nonsyndromic hearing loss (ARNSHL) features a high degree of genetic heterogeneity. Many genes responsible for ARNSHL have been identified or mapped. We previously mapped an ARNSHL locus at 17q12, herein designated DFNB99, in a consanguineous Chinese family. In this study, whole‐exome sequencing revealed a homozygous missense mutation (c.1259G>A, p.Arg420Gln) in the gene‐encoding transmembrane protein 132E (TMEM132E) as the causative variant. Immunofluorescence staining of the Organ of Corti showed Tmem132e highly expressed in murine inner hair cells. Furthermore, knockdown of the tmem132e ortholog in zebrafish affected the mechanotransduction of hair cells. Finally, wild‐type human TMEM132E mRNA, but not the mRNA carrying the c.1259G>A mutation rescued the Tmem132e knockdown phenotype. We conclude that the variant in TMEM132E is the most likely cause of DFNB99.     

Anti‐HLA alloantibodies of the IgA isotype in re‐transplant candidates part II: Correlation with graft survival

We reported previously on the widespread occurrence of anti‐HLA alloantibodies of the IgA isotype (anti‐HLA IgA) in the sera of solid‐organ re‐transplantation (re‐tx) candidates (Arnold et al., 2013 ). Specifically focussing on kidney re‐tx patients, we now extended our earlier findings by examining the impact of the presence and donor specificity of anti‐HLA IgA on graft survival. We observed frequent concurrence of anti‐HLA IgA and anti‐HLA IgG in 27% of our multicenter collective of 694 kidney re‐tx patients. This subgroup displayed significantly reduced graft survival as evidenced by the median time to first dialysis after transplantation (TTD 77 months) compared to patients carrying either anti‐HLA IgG or IgA (TTD 102 and 94 months, respectively). In addition, donor specificity of anti‐HLA IgA had a significant negative impact on graft survival (TTD 74 months) in our study. Taken together, our data strongly indicate that presence of anti‐HLA IgA, in particular in conjunction with anti‐HLA‐IgG, in sera of kidney re‐tx patients is associated with negative transplantation outcome.     

Trichothiodystrophy, mental retardation, short stature, ataxia, and gonadal dysfunction in three Moroccan siblings

Three sibs, a boy and two girls, born to Moroccan consanguineous parents, were affected with a syndrome characterized by brittle hair, mental retardation, short stature, ataxia, and gonadal dysfunction. The hair in these three patients displayed the morphological and biochemical hallmarks of trichothiodystrophy (TTD). Gonadal function tests showed abnormal gonadotropic responses to LHRH, consistent with delayed puberty in the male and ovarian failure in both females. Comparison with previously reported cases of TTD associated with mental retardation suggests genetic heterogeneity, although specific biochemical markers are needed in order to answer this question.     

Novel homozygous mutation in DSP causing skin fragility–woolly hair syndrome: report of a large family and review of the desmoplakin‐related phenotypes

Al‐Owain M, Wakil S, Shareef F, Al‐Fatani A, Hamadah E, Haider M, Al‐Hindi H, Awaji A, Khalifa O, Baz B, Ramadhan R, Meyer B. Novel homozygous mutation in DSP causing skin fragility–woolly hair syndrome: report of a large family and review of the desmoplakin‐related phenotypes. Desmoplakin is an important cytoskeletal linker for the function of the desmosomes. Linking desmoplakin to certain types of cardiocutaneous syndromes has been a hot topic recently. Skin fragility–woolly hair syndrome is a rare autosomal recessive disorder involving the desmosomes and is caused by mutation in the desmoplakin gene (DSP). We report five members from a large family with skin fragility–woolly hair syndrome. The index is a 14‐year‐old girl with palmoplantar keratoderma, woolly hair, variable alopecia, dystrophic nails, and excessive blistering to trivial mechanical trauma. No cardiac symptoms were reported. Although formal cardiac examination was not feasible, the echocardiographic evaluation of the other two affected younger siblings was normal. Homozygosity mapping and linkage analysis revealed a high LOD score region in the short arm of chromosome 6 that harbors the DSP. Full sequencing of the DSP showed a novel homozygous c.7097 G>A (p.R2366H) mutation in all affected members, and the parents were heterozygous. This is the report of the third case/family of the skin fragility–woolly hair syndrome in the literature. We also present a clinical and molecular review of various desmoplakin‐related phenotypes, with emphasis on onset of cardiomyopathy. The complexity of the desmoplakin and its variable presentations warrant introducing the term ‘desmoplakinopathies’ to describe all the phenotypes related to defects in the desmoplakin.     

Trichothiodystrophy: a systematic review of 112 published cases characterises a wide spectrum of clinical manifestations

Trichothiodystrophy (TTD) is a rare, autosomal recessive disease, characterised by brittle, sulfur deficient hair and multisystem abnormalities. A systematic literature review identified 112 patients ranging from 12 weeks to 47 years of age (median 6 years). In addition to hair abnormalities, common features reported were developmental delay/intellectual impairment (86%), short stature (73%), ichthyosis (65%), abnormal characteristics at birth (55%), ocular abnormalities (51%), infections (46%), photosensitivity (42%), maternal pregnancy complications (28%) and defective DNA repair (37%). There was high mortality, with 19 deaths under the age of 10 years (13 infection related), which is 20-fold higher compared to the US population. The spectrum of clinical features varied from mild disease with only hair involvement to severe disease with profound developmental defects, recurrent infections and a high mortality at a young age. Abnormal characteristics at birth and pregnancy complications, unrecognised but common features of TTD, suggest a role for DNA repair genes in normal fetal development.     

Cartilage‐hair hypoplasia with normal height in childhood—4 patients with a unique genotype

The manifestations of cartilage‐hair hypoplasia (CHH), a metaphyseal chondrodysplasia caused by RMRP mutations, include short stature, hypoplastic hair, immunodeficiency and increased risk of malignancies. Clinical features show significant variability. We report a patient with normal height until age 12.5 years (?1.6 SDS at 11 years) who was diagnosed with CHH at 14 years. RMRP sequencing revealed compound heterozygosity for g.70A>G mutation and a 10‐nucleotide duplication at position ?13 (TACTCTGTGA). Through the Finnish Skeletal Dysplasia Register, we identified 3 additional patients with identical genotype. Two of them also showed unusually mild growth failure (height SDS ?1.6 at 14 years and ?3.0 at 12 years, respectively). Three of the 4 patients suffered from recurrent infections; 1 developed progressive bronchiectasis and another died from aggressive lymphoma. Our findings expand the phenotypic variability in CHH to include normal childhood height. The milder growth retardation related to this particular genotype was not associated with less severe extra‐skeletal manifestations, emphasizing the need for careful follow‐up also in CHH patients with mild‐skeletal manifestations.     

Chondrocyte‐specific Smad4 gene conditional knockout results in hearing loss and inner ear malformation in mice

Smad4 is the central intracellular mediator of transforming growth factor‐β (TGF‐β) signaling, which plays crucial roles in tissue regeneration, cell differentiation, embryonic development, and regulation of the immune system. Conventional Smad4 gene knockout results in embryonic lethality, precluding its use in studies of the role of Smad4 in inner ear development. We used chondrocyte‐specific Smad4 knockout mice (Smad4^Co/Co) to investigate the function of Smad4 in inner ear development. Smad4^Co/Co mice were characterized by a smaller cochlear volume, bone malformation, and abnormalities of the osseous spiral lamina and basilar membrane. The development of the hair cells was also abnormal, as evidenced by the disorganized stereocilia and reduced density of the neuronal processes beneath the hair cells. Auditory function tests revealed the homozygous Smad4^Co/Co mice suffered from severe sensorineural hearing loss. Our results suggest that Smad4 is required for inner ear development and normal auditory function in mammals. Developmental Dynamics, 2009. © 2009 Wiley‐Liss, Inc.