Deletion of 2 amino acids in IHH in a Japanese family with brachydactyly type A1.

BACKGROUND: Brachydactyly type A1 (BDA1) is an autosomal dominant disorder characterized by uniform shortening of the middle phalanges in all digits. It is associated with variants in the Indian Hedgehog (IHH) gene, which plays a key role in endochondral ossification. To date, heterozygous pathogenic IHH variants involving several codons, which are restricted to a specific region of the N-terminal active fragment of IHH, have been reported. The purpose of this study was to identify the pathogenic variant in a Japanese family with BDA1 and to evaluate its pathogenesis with regard to previous reports. METHODS: The proband, a 9-year-old boy, his siblings, and his father had shortened digits and a short stature of variable severity. Based on physical examinations, radiographic findings and family history, they were diagnosed with BDA1. This family is the first case of an isolated malformation in Japan. Sanger sequencing of IHH was performed on these individuals and on the proband's unaffected mother. The significance of the variants was assessed using three-dimensional analysis methods. RESULTS: Sanger sequencing showed a novel IHH heterozygous variant, NM_002181.4:c.544_549delTCAAAG(p.Ser182Lys183del) [NC_000002.12:g.219057461_219057466del].. These two residues are located outside the cluster region considered a hotspot of pathogenic variants. Three-dimensional modelling showed that S182 and K183 are located on the same surface as other residues associated with BDA1. Analysis of residue interactions across the interface between IHH and its interacting receptor protein revealed the presence of hydrogen bonds between them. CONCLUSIONS: We report a novel variant, NM_002181.4:c.544_549delTCAAAG (p.Ser182Lys183del) [NC_000002.12:g.219057461_219057466del] in a Japanese family with BDA1. Indeed, neither variations in codons 182 or 183 nor with such two-amino-acid deletions in IHH have been reported previously. Although these two residues are located outside the cluster region considered a hotspot of pathogenic variants, we speculate that this variant causes BDA1 through impaired interactions between IHH and target receptor proteins in the same manner as other pathogenic variants located in the cluster region. This report expands the genetic spectrum of BDA1.

Eye-Mouth Associated Movement in the Human Newborn and Very Young Infant.

BACKGROUND: The aim of this study is to demonstrate that goal-directed eye-mouth associated movement exists in the newborn and very young infant. METHODS: The participants were 17 healthy term newborns or very young infants whose ages at the time of the first examination ranged from 1 to 24 days. The examiner held the tip of an index finger 20 to 30 cm in front of a participant's mouth, then suddenly moved it directly toward the mouth. Thirteen of the participants were also examined with the examiner's palm as the visual stimulus. The response was judged to be positive if clear mouth opening was elicited as the fingertip or palm was approaching the mouth. RESULTS: In the examinations using a fingertip, the frequency of a positive response as to the total number of examinations in the different age groups within the first two months of life ranged between 43.9% and 48.8%, and precipitously decreased to 6.3% at two months of age. A positive response was not elicited from age three months. On the other hand, in the examinations using a palm, the frequency of a positive response was 5.0% in the newborns, and 6.7% in the infants aged between seven days and one month. A positive response was never obtained from two months of age. CONCLUSION: This study demonstrated that visually guided mouth opening toward an approaching target exists in the human newborn. The eye-mouth associated movement may be controlled through rudimentary but functional visuomotor circuits in the brain interconnecting different cortices.

Sudden death from systemic rotavirus infection and detection of nonstructural rotavirus proteins.

A 2.5-year-old girl died suddenly during the course of rotavirus gastroenteritis. The autopsy showed encephalopathy with rotavirus systemic infection. Here, we provide evidence of rotavirus replication in multiple organs. Our findings clarify that rotavirus infection in children can extend beyond the intestinal tract through viremia.