Abstract

Background: Isolated congenital nail clubbing (ICNC) is a rare autosomal recessive disorder characterised by enlargement of the terminal segments of fingers and toes with thickened nails due to proliferation of the connective tissues and abnormal function of the nail matrix. In the present study, we investigated a large Pakistani family with 11 affected individuals having hereditary congenital nail clubbing as a single invariable clinical feature without any associated ectodermal, skeletal or systemic imperfection.

Objective: To identify a gene underlying the ICNC phenotype.

Methods: A genome wide homozygosity linkage mapping strategy was used to identify the gene causing ICNC. DNA sequencing was performed to screen 10 candidate genes located in the linkage interval.

Results: We assigned the disease locus for the ICNC to a 13.25 cM region on chromosome 4q32.3–q34.1. This region corresponds to 12.27 Mbp according to the sequence based physical map (Build 36.1) and flanked by markers D4S2952 and D4S415. A maximum two point LOD score of 2.98 (θ = 0.00) was obtained at marker D4S2368 while a maximum multipoint LOD score of 3.62 was obtained with several markers along the disease interval. Sequence analysis of the candidate genes, in the ICNC linkage interval, revealed a homozygous missense mutation (c.577T>C; p.S193P) in exon 6 of the human HPGD gene encoding NAD⁺ dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH).

Conclusions: The involvement of 15-PGDH in the pathogenesis of ICNC may open up interesting perspectives into the function of this enzyme in nail morphogenesis/development.